Alcohol consumption and the risk of type 2 diabetes mellitus: effect modification by hypercholesterolemia: the Third Korea National Health and Nutrition Examination Survey (2005).

PubMed

Jang, Hyeongap; Jang, Won-Mo; Park, Jong-Heon; Oh, Juhwan; Oh, Mu-Kyung; Hwang, Soo-Hee; Kim, Yong-Ik; Lee, Jin-Seok

2012-01-01

While the protective nature of moderate alcohol consumption against diabetes mellitus is well known, inconsistent findings continue to be reported. The possibility of different mixes of effect modifiers has been raised as a reason for those inconsistent findings. Our study aim was to examine potential effect modifiers that can change the effect of alcohol consumption on type 2 diabetes. From data in the third Korea National Health and Nutrition Examination Survey, 3,982 individuals over the age of 30 years who had not been diagnosed with diabetes were selected for inclusion in the study population. Breslow and Day's test and the Wald test between hypercholesterolemia and alcohol consumption in a multiple logistic regression model were used to assess effect modification. Odds ratios for diabetes stratified by alcohol consumption strata and assessed using Breslow and Day's tests for homogeneity indicated that hypercholesterolemia was not a significant confounding factor (p=0.01). However, the Wald test for interaction terms, which is a conservative method of effect modification, was significant (p=0.03). The results indicate that moderate alcohol consumption is not necessarily protective for type 2 diabetes mellitus, if a person has hypercholesterolemia. People who have hypercholesterolemia should be aware of the risk associated with alcohol consumption, a risk that contrasts with the reported protective effect of moderate alcohol consumption on diabetes.

Factors associated with employment status before and during pregnancy: Implications for studies of pregnancy outcomes.

PubMed

Rocheleau, Carissa M; Bertke, Stephen J; Lawson, Christina C; Romitti, Paul A; Desrosiers, Tania A; Agopian, Aaron J; Bell, Erin; Gilboa, Suzanne M

2017-04-01

Potential confounding or effect modification by employment status is frequently overlooked in pregnancy outcome studies. To characterize how employed and non-employed women differ, we compared demographics, behaviors, and reproductive histories by maternal employment status for 8,343 mothers of control (non-malformed) infants in the National Birth Defects Prevention Study (1997-2007) and developed a multivariable model for employment status anytime during pregnancy and the 3 months before conception. Sixteen factors were independently associated with employment before or during pregnancy, including: maternal age, pre-pregnancy body mass index, pregnancy intention, periconceptional/first trimester smoking and alcohol consumption, and household income. Employment status was significantly associated with many common risk factors for adverse pregnancy outcomes. Pregnancy outcome studies should consider adjustment or stratification by employment status. In studies of occupational exposures, these differences may cause uncontrollable confounding if non-employed women are treated as unexposed instead of excluded from analysis. Am. J. Ind. Med. 60:329-341, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Astronomy Matters for Chemistry Teachers.

ERIC Educational Resources Information Center

Huebner, Jay S.; And Others

1996-01-01

Describes basic misconceptions about the origin of elements and forms of matter found in chemistry texts that need modification in light of modern observational data and interpretations given in astronomy. Notes that there are forms of matter other than elements and compounds. Confounding examples from astronomy include white dwarfs, neutron…

Increased Mortality in Groups of Cattle Administered the β-Adrenergic Agonists Ractopamine Hydrochloride and Zilpaterol Hydrochloride

PubMed Central

Loneragan, Guy H.; Thomson, Daniel U.; Scott, H. Morgan

2014-01-01

The United States Food and Drug Administration (FDA) approved two β-adrenergic agonists (βAA) for in-feed administration to cattle fed in confinement for human consumption. Anecdotal reports have generated concern that administration of βAA might be associated with an increased incidence of cattle deaths. Our objectives, therefore, were to a) quantify the association between βAA administration and mortality in feedlot cattle, and b) explore those variables that may confound or modify this association. Three datasets were acquired for analysis: one included information from randomized and controlled clinical trials of the βAA ractopamine hydrochloride, while the other two were observational data on zilpaterol hydrochloride administration to large numbers of cattle housed, fed, and cared for using routine commercial production practices in the U.S. Various population and time at-risk models were developed to explore potential βAA relationships with mortality, as well as the extent of confounding and effect modification. Measures of effect were relatively consistent across datasets and models in that the cumulative risk and incidence rate of death was 75 to 90% greater in animals administered the βAA compared to contemporaneous controls. During the exposure period, 40 to 50% of deaths among groups administered the βAA were attributed to administration of the drug. None of the available covariates meaningfully confounded the relationship between βAA and increased mortality. Only month of slaughter, presumably a proxy for climate, consistently modified the effect in that the biological association was generally greatest during the warmer months of the year. While death is a rare event in feedlot cattle, the data reported herein provide compelling evidence that mortality is nevertheless increased in response to administration of FDA-approved βAA and represents a heretofore unquantified adverse drug event. PMID:24621596

Optimizing complex phenotypes through model-guided multiplex genome engineering

DOE PAGES

Kuznetsov, Gleb; Goodman, Daniel B.; Filsinger, Gabriel T.; ...

2017-05-25

Here, we present a method for identifying genomic modifications that optimize a complex phenotype through multiplex genome engineering and predictive modeling. We apply our method to identify six single nucleotide mutations that recover 59% of the fitness defect exhibited by the 63-codon E. coli strain C321.ΔA. By introducing targeted combinations of changes in multiplex we generate rich genotypic and phenotypic diversity and characterize clones using whole-genome sequencing and doubling time measurements. Regularized multivariate linear regression accurately quantifies individual allelic effects and overcomes bias from hitchhiking mutations and context-dependence of genome editing efficiency that would confound other strategies.

Optimizing complex phenotypes through model-guided multiplex genome engineering

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuznetsov, Gleb; Goodman, Daniel B.; Filsinger, Gabriel T.

Here, we present a method for identifying genomic modifications that optimize a complex phenotype through multiplex genome engineering and predictive modeling. We apply our method to identify six single nucleotide mutations that recover 59% of the fitness defect exhibited by the 63-codon E. coli strain C321.ΔA. By introducing targeted combinations of changes in multiplex we generate rich genotypic and phenotypic diversity and characterize clones using whole-genome sequencing and doubling time measurements. Regularized multivariate linear regression accurately quantifies individual allelic effects and overcomes bias from hitchhiking mutations and context-dependence of genome editing efficiency that would confound other strategies.

Infrared spectroscopic imaging detects chemical modifications in liver fibrosis due to diabetes and disease

PubMed Central

Sreedhar, Hari; Varma, Vishal K.; Gambacorta, Francesca V.; Guzman, Grace; Walsh, Michael J.

2016-01-01

The importance of stroma as a rich diagnostic region in tissue biopsies is growing as there is an increasing understanding that disease processes in multiple organs can affect the composition of adjacent connective tissue regions. This may be especially true in the liver, since this organ’s central metabolic role exposes it to multiple disease processes. We use quantum cascade laser infrared spectroscopic imaging to study changes in the chemical status of hepatocytes and fibrotic regions of liver tissue that result from the progression of liver cirrhosis to hepatocellular carcinoma and the potentially confounding effects of diabetes mellitus. PMID:27375956

Ambient air pollution, lung function, and airway responsiveness in asthmatic children.

PubMed

Ierodiakonou, Despo; Zanobetti, Antonella; Coull, Brent A; Melly, Steve; Postma, Dirkje S; Boezen, H Marike; Vonk, Judith M; Williams, Paul V; Shapiro, Gail G; McKone, Edward F; Hallstrand, Teal S; Koenig, Jane Q; Schildcrout, Jonathan S; Lumley, Thomas; Fuhlbrigge, Anne N; Koutrakis, Petros; Schwartz, Joel; Weiss, Scott T; Gold, Diane R

2016-02-01

Although ambient air pollution has been linked to reduced lung function in healthy children, longitudinal analyses of pollution effects in asthmatic patients are lacking. We sought to investigate pollution effects in a longitudinal asthma study and effect modification by controller medications. We examined associations of lung function and methacholine responsiveness (PC20) with ozone, carbon monoxide (CO), nitrogen dioxide, and sulfur dioxide concentrations in 1003 asthmatic children participating in a 4-year clinical trial. We further investigated whether budesonide and nedocromil modified pollution effects. Daily pollutant concentrations were linked to ZIP/postal code of residence. Linear mixed models tested associations of within-subject pollutant concentrations with FEV1 and forced vital capacity (FVC) percent predicted, FEV1/FVC ratio, and PC20, adjusting for seasonality and confounders. Same-day and 1-week average CO concentrations were negatively associated with postbronchodilator percent predicted FEV1 (change per interquartile range, -0.33 [95% CI, -0.49 to -0.16] and -0.41 [95% CI, -0.62 to -0.21], respectively) and FVC (-0.19 [95% CI, -0.25 to -0.07] and -0.25 [95% CI, -0.43 to -0.07], respectively). Longer-term 4-month CO averages were negatively associated with prebronchodilator percent predicted FEV1 and FVC (-0.36 [95% CI, -0.62 to -0.10] and -0.21 [95% CI, -0.42 to -0.01], respectively). Four-month averaged CO and ozone concentrations were negatively associated with FEV1/FVC ratio (P < .05). Increased 4-month average nitrogen dioxide concentrations were associated with reduced postbronchodilator FEV1 and FVC percent predicted. Long-term exposures to sulfur dioxide were associated with reduced PC20 (percent change per interquartile range, -6% [95% CI, -11% to -1.5%]). Treatment augmented the negative short-term CO effect on PC20. Air pollution adversely influences lung function and PC20 in asthmatic children. Treatment with controller medications might not protect but rather worsens the effects of CO on PC20. This clinical trial design evaluates modification of pollution effects by treatment without confounding by indication. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Ambient air pollution, lung function and airway responsiveness in children with asthma

PubMed Central

Ierodiakonou, Despo; Zanobetti, Antonella; Coull, Brent A.; Melly, Steve; Postma, Dirkje S.; Boezen, H. Marike; Vonk, Judith M.; Williams, Paul V.; Shapiro, Gail G.; McKone, Edward F.; Hallstrand, Teal S.; Koenig, Jane Q.; Schildcrout, Jonathan S.; Lumley, Thomas; Fuhlbrigge, Anne N.; Koutrakis, Petros; Schwartz, Joel; Weiss, Scott T.; Gold, Diane R

2016-01-01

Background Although ambient air pollution has been linked to reduced lung function in healthy children, longitudinal analyses of pollution effects in asthma are lacking. Objective To investigate pollution effects in a longitudinal asthma study and effect modification by controller medications. Methods We examined associations of lung function and methacholine responsiveness (PC20) with ozone, carbon monoxide (CO), nitrogen dioxide (NO2) and sulfur dioxide (SO2) levels in 1,003 asthmatic children participating in a 4-year clinical trial. We further investigated whether budesonide and nedocromil modified pollution effects. Daily pollutant concentrations were linked to zip/postal code of residence. Linear mixed models tested associations of within-subject pollutant concentrations with FEV1 and FVC %predicted, FEV1/FVC and PC20, adjusting for seasonality and confounders. Results Same-day and 1-week average CO levels were negatively associated with post-bronchodilator %predicted FEV1 (change(95%CI) per IQR: −0.33(−0.49, −0.16), −0.41(−0.62, −0.21), respectively) and FVC (−0.19(−0.25, −0.07), −0.25(−0.43, −0.07)). Longer-term four-month averages of CO were negatively associated with prebronchodilator %predicted FEV1 and FVC (−0.36(−0.62, −0.10), −0.21(−0.42, −0.01)). Four-month averaged CO and ozone levels were negatively associated with FEV1/FVC (p<0.05). Increased four-month average NO2 levels were associated with reduced post-bronchodilator FEV1 and FVC %predicted. Long-term exposures to SO2 were associated with reduced PC20 (%change(95%CI) per IQR:-6(-11,-1.5)). Treatment augmented the negative short-term CO effect on PC20. Conclusions Air pollution adversely influences lung function and PC20 in asthmatic children. Treatment with controller medications may not protect but worsens the CO effects on PC20. This clinical trial design evaluates modification of pollution effects by treatment without confounding by indication. PMID:26187234

Evidence for a neural correlate of a framing effect: bias-specific activity in the ventromedial prefrontal cortex during credibility judgments.

PubMed

Deppe, M; Schwindt, W; Krämer, J; Kugel, H; Plassmann, H; Kenning, P; Ringelstein, E B

2005-11-15

Neural processes within the medial prefrontal cortex play a crucial role in assessing and integrating emotional and other implicit information during decision-making. Phylogenetically, it was important for the individual to assess the relevance of all kinds of environmental stimuli in order to adapt behavior in a flexible manner. Consequently, we can in principle not exclude that environmental information covertly influences the evaluation of actually decision relevant facts ("framing effect"). To test the hypothesis that the medial prefrontal cortex is involved into a framing effect we employed functional magnetic resonance imaging (fMRI) during a binary credibility judgment task. Twenty-one subjects were asked to judge 30 normalized news magazine headlines by forced answers as "true" or "false". To confound the judgments by formally irrelevant framing information we presented each of the headlines in four different news magazines characterized by varying credibility. For each subject the susceptibility to the judgment confounder (framing information) was assessed by magazine-specific modifications of the answers given. We could show that individual activity changes of the ventromedial prefrontal cortex during the judgments correlate with the degree of an individual's susceptibility to the framing information. We found (i) a neural correlate of a framing effect as postulated by behavioral decision theorists that (ii) reflects interindividual differences in the degree of the susceptibility to framing information.

Poppers, Kaposi's sarcoma, and HIV infection: empirical example of a strong confounding effect?

PubMed

Morabia, A

1995-01-01

Are there empirical examples of strong confounding effects? Textbooks usually show examples of weak confounding or use hypothetical examples of strong confounding to illustrate the paradoxical consequences of not separating out the effect of the studied exposure from that of second factor acting as a confounder. HIV infection is a candidate strong confounder of the spuriously high association reported between consumption of poppers, a sexual stimulant, and risk of Kaposi's sarcoma in the early phase of the AIDS epidemic. To examine this hypothesis, assumptions must be made on the prevalence of HIV infection among cases of Kaposi's sarcoma and on the prevalence of heavy popper consumption according to HIV infection in cases and controls. Results show that HIV infection may have confounded the poppers-Kaposi's sarcoma association. However, it cannot be ruled out that HIV did not qualify as a confounder because it was either an intermediate variable or an effect modifier of the association between popper inhalation and Kaposi's sarcoma. This example provides a basis to discuss the mechanism by which confounding occurs as well as the practical importance of confounding in epidemiologic research.

Invited commentary: boundless science--putting natural direct and indirect effects in a clearer empirical context.

PubMed

Naimi, Ashley I

2015-07-15

Epidemiologists are increasingly using natural effects for applied mediation analyses, yet 1 key identifying assumption is unintuitive and subject to some controversy. In this issue of the Journal, Jiang and VanderWeele (Am J Epidemiol. 2015;182(2):105-108) formalize the conditions under which the difference method can be used to estimate natural indirect effects. In this commentary, I discuss implications of the controversial "cross-worlds" independence assumption needed to identify natural effects. I argue that with a binary mediator, a simple modification of the authors' approach will provide bounds for natural direct and indirect effect estimates that better reflect the capacity of the available data to support empirical statements on the presence of mediated effects. I discuss complications encountered when odds ratios are used to decompose effects, as well as the implications of incorrectly assuming the absence of exposure-induced mediator-outcome confounders. I note that the former problem can be entirely resolved using collapsible measures of effect, such as risk ratios. In the Appendix, I use previous derivations for natural direct effect bounds on the risk difference scale to provide bounds on the odds ratio scale that accommodate 1) uncertainty due to the cross-world independence assumption and 2) uncertainty due to the cross-world independence assumption and the presence of exposure-induced mediator-outcome confounders. © The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Use of logistic regression for modelling risk factors: with application to non-melanoma skin cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vitaliano, P.P.

Logistic regression was used to estimate the relative risk of basal and squamous skin cancer for such factors as cumulative lifetime solar exposure, age, complexion, and tannability. In previous reports, a subject's exposure was estimated indirectly, by latitude, or by the number of sun days in a subject's habitat. In contrast, these results are based on interview data gathered for each subject. A relatively new technique was used to estimate relative risk by controlling for confounding and testing for effect modification. A linear effect for the relative risk of cancer versus exposure was found. Tannability was shown to be amore » more important risk factor than complexion. This result is consistent with the work of Silverstone and Searle.« less

An overview of confounding. Part 1: the concept and how to address it.

PubMed

Howards, Penelope P

2018-04-01

Confounding is an important source of bias, but it is often misunderstood. We consider how confounding occurs and how to address confounding using examples. Study results are confounded when the effect of the exposure on the outcome, mixes with the effects of other risk and protective factors for the outcome. This problem arises when these factors are present to different degrees among the exposed and unexposed study participants, but not all differences between the groups result in confounding. Thinking about an ideal study where all of the population of interest is exposed in one universe and is unexposed in a parallel universe helps to distinguish confounders from other differences. In an actual study, an observed unexposed population is chosen to stand in for the unobserved parallel universe. Differences between this substitute population and the parallel universe result in confounding. Confounding by identified factors can be addressed analytically and through study design, but only randomization has the potential to address confounding by unmeasured factors. Nevertheless, a given randomized study may still be confounded. Confounded study results can lead to incorrect conclusions about the effect of the exposure of interest on the outcome. © 2018 Nordic Federation of Societies of Obstetrics and Gynecology.

Examining the Error of Mis-Specifying Nonlinear Confounding Effect with Application on Accelerometer-Measured Physical Activity

ERIC Educational Resources Information Center

Lee, Paul H.

2017-01-01

Purpose: Some confounders are nonlinearly associated with dependent variables, but they are often adjusted using a linear term. The purpose of this study was to examine the error of mis-specifying the nonlinear confounding effect. Methods: We carried out a simulation study to investigate the effect of adjusting for a nonlinear confounder in the…

Examining the Error of Mis-Specifying Nonlinear Confounding Effect With Application on Accelerometer-Measured Physical Activity.

PubMed

Lee, Paul H

2017-06-01

Some confounders are nonlinearly associated with dependent variables, but they are often adjusted using a linear term. The purpose of this study was to examine the error of mis-specifying the nonlinear confounding effect. We carried out a simulation study to investigate the effect of adjusting for a nonlinear confounder in the estimation of a causal relationship between the exposure and outcome in 3 ways: using a linear term, binning into 5 equal-size categories, or using a restricted cubic spline of the confounder. Continuous, binary, and survival outcomes were simulated. We examined the confounder across varying measurement error. In addition, we performed a real data analysis examining the 3 strategies to handle the nonlinear effects of accelerometer-measured physical activity in the National Health and Nutrition Examination Survey 2003-2006 data. The mis-specification of a nonlinear confounder had little impact on causal effect estimation for continuous outcomes. For binary and survival outcomes, this mis-specification introduced bias, which could be eliminated using spline adjustment only when there is small measurement error of the confounder. Real data analysis showed that the associations between high blood pressure, high cholesterol, and diabetes and mortality adjusted for physical activity with restricted cubic spline were about 3% to 11% larger than their counterparts adjusted with a linear term. For continuous outcomes, confounders with nonlinear effects can be adjusting with a linear term. Spline adjustment should be used for binary and survival outcomes on confounders with small measurement error.

Effect modification by vitamin D receptor genetic polymorphisms in the association between cumulative lead exposure and pulse pressure: a longitudinal study.

PubMed

Jhun, Min A; Hu, Howard; Schwartz, Joel; Weisskopf, Marc G; Nie, Linda H; Sparrow, David; Vokonas, Pantel S; Park, Sung Kyun

2015-01-13

Although the association between lead and cardiovascular disease is well established, potential mechanisms are still poorly understood. Calcium metabolism plays a role in lead toxicity and thus, vitamin D receptor (VDR) polymorphisms have been suggested to modulate the association between lead and health outcomes. We investigated effect modification by VDR genetic polymorphisms in the association between cumulative lead exposure and pulse pressure, a marker of arterial stiffness. We examined 727 participants (3,100 observations from follow-ups from 1991 to 2011) from the Normative Aging Study (NAS), a longitudinal study of aging. Tibia and patella bone lead levels were measured using K-x-ray fluorescence. Four single nucleotide polymorphisms (SNPs) in the VDR gene, Bsm1, Taq1, Apa1, and Fok1, were genotyped. Linear mixed effects models with random intercepts were implemented to take into account repeated measurements. Adjusting for potential confounders, pulse pressure was 2.5 mmHg (95% CI: 0.4-4.7) and 1.9 mmHg (95% CI: 0.1-3.8) greater per interquartile range (IQR) increase in tibia lead (15 μg/g) and patella lead (20 μg/g), respectively, in those with at least one minor frequency allele in Bsm1 compared with those with major frequency allele homozygotes. The observed interaction effect between bone lead and the Bsm1 genotype persists over time during the follow-up. Similar results were observed in effect modification by Taq1. This study suggests that subjects with the minor frequency alleles of VDR Bsm1 or Taq1 may be more susceptible to cumulative lead exposure-related elevated pulse pressure.

An evidence-based approach to globally assess the covariate-dependent effect of the MTHFR single nucleotide polymorphism rs1801133 on blood homocysteine: a systematic review and meta-analysis.

PubMed

Jin, Huifeng; Cheng, Haojie; Chen, Wei; Sheng, Xiaoming; Levy, Mark A; Brown, Mark J; Tian, Junqiang

2018-05-01

The single nucleotide polymorphism of the gene 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T (or rs1801133) is the most established genetic factor that increases plasma total homocysteine (tHcy) and consequently results in hyperhomocysteinemia. Yet, given the limited penetrance of this genetic variant, it is necessary to individually predict the risk of hyperhomocysteinemia for an rs1801133 carrier. We hypothesized that variability in this genetic risk is largely due to the presence of factors (covariates) that serve as effect modifiers, confounders, or both, such as folic acid (FA) intake, and aimed to assess this risk in the complex context of these covariates. We systematically extracted from published studies the data on tHcy, rs1801133, and any previously reported rs1801133 covariates. The resulting metadata set was first used to analyze the covariates' modifying effect by meta-regression and other statistical means. Subsequently, we controlled for this modifying effect by genotype-stratifying tHcy data and analyzed the variability in the risk resulting from the confounding of covariates. The data set contains data on 36 rs1801133 covariates that were collected from 114,799 participants and 256 qualified studies, among which 6 covariates (sex, age, race, FA intake, smoking, and alcohol consumption) are the most frequently informed and therefore included for statistical analysis. The effect of rs1801133 on tHcy exhibits significant variability that can be attributed to effect modification as well as confounding by these covariates. Via statistical modeling, we predicted the covariate-dependent risk of tHcy elevation and hyperhomocysteinemia in a systematic manner. We showed an evidence-based approach that globally assesses the covariate-dependent effect of rs1801133 on tHcy. The results should assist clinicians in interpreting the rs1801133 data from genetic testing for their patients. Such information is also important for the public, who increasingly receive genetic data from commercial services without interpretation of its clinical relevance. This study was registered at Research Registry with the registration number reviewregistry328.

An overview of confounding. Part 2: how to identify it and special situations.

PubMed

Howards, Penelope P

2018-04-01

Confounding biases study results when the effect of the exposure on the outcome mixes with the effects of other risk and protective factors for the outcome that are present differentially by exposure status. However, not all differences between the exposed and unexposed group cause confounding. Thus, sources of confounding must be identified before they can be addressed. Confounding is absent in an ideal study where all of the population of interest is exposed in one universe and is unexposed in a parallel universe. In an actual study, an observed unexposed population represents the unobserved parallel universe. Thinking about differences between this substitute population and the unexposed parallel universe helps identify sources of confounding. These differences can then be represented in a diagram that shows how risk and protective factors for the outcome are related to the exposure. Sources of confounding identified in the diagram should be addressed analytically and through study design. However, treating all factors that differ by exposure status as confounders without considering the structure of their relation to the exposure can introduce bias. For example, conditions affected by the exposure are not confounders. There are also special types of confounding, such as time-varying confounding and unfixable confounding. It is important to evaluate carefully whether factors of interest contribute to confounding because bias can be introduced both by ignoring potential confounders and by adjusting for factors that are not confounders. The resulting bias can result in misleading conclusions about the effect of the exposure of interest on the outcome. © 2018 Nordic Federation of Societies of Obstetrics and Gynecology.

Edge and area effects on the occurrence of migrant forest songbirds

USGS Publications Warehouse

Parker, T.H.; Stansberry, B.M.; Becker, C.D.; Gipson, P.S.

2005-01-01

Concerns about forest fragmentation and its conservation implications have motivated numerous studies that investigate the influence of forest patch area and forest edge on songbird distribution patterns. The generalized effects of forest patch size and forest edge on animal distributions is still debatable because forest patch size and forest edge are often confounded and because of an incomplete synthesis of available data. To fill a portion of this gap, we incorporated all available published data (33 papers) in meta-analyses of forest edge and area effects on site occupancy patterns for 26 Neotropical migrant forest-nesting songbirds in eastern North America. All reported area effects are confounded or potentially confounded by edge effects, and we refer to these as "confounded" studies. The converse, however, is not true and most reported edge effects are independent of patch area. When considering only nonconfounded studies of edge effects, only 1 of 17 species showed significant edge avoidance and 3 had significant affinity for edges. In confounded studies, 12 of 22 species showed significant avoidance of small patches and edges, and 1 had an affinity for small patches and edges. Furthermore, average effect sizes averaged across studies or species tended to be higher for confounded studies than for edge studies. We discuss three possible reasons for differences in results between these two groups of studies. First, studies of edge effects tended to be carried out in landscapes with greater forest cover than studies of confounded effects; among confounded effects studies, as forest cover increased, we observed a nonsignificant trend towards decreasing strength of small patch or edge avoidance effects. Thus, the weaker effects in edge studies may be due to the fact that these studies were conducted in forest-dominated landscapes. Second, we may have detected strong effects only in confounded studies because area effects are much stronger than edge effects on bird occurrence, and area effects drive the results in confounded studies. Third, edge and area effects may interact in such a way that edge effects become more important as forest patch size decreases; thus, both edge and area effects are responsible for results in confounded studies. These three explanations cannot be adequately separated with existing data. Regardless, it is clear that fragmentation of forests into small patches is detrimental to many migrant songbird species. ??2005 Society for Conservation Biology.

Spatial variation in attributable risks.

PubMed

Congdon, Peter

2015-01-01

The attributable risk (AR) measures the contribution of a particular risk factor to a disease, and allows estimation of disease rates specific to that risk. While previous studies consider variability in ARs over demographic categories, this paper considers the extent of spatial variability in ARs estimated from multilevel data with confounders both at individual and geographic levels. A case study considers the AR for diabetes in relation to elevated BMI, and area rates for diabetes attributable to excess weight. Contextual adjustment includes known area variables, and unobserved spatially clustered influences, while spatial heterogeneity (effect modification) is considered in terms of varying effects of elevated BMI by neighbourhood deprivation category. The application is to patient register data in London, with clear evidence of spatial variation in ARs, and in small area diabetes rates attributable to excess weight. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Problem of Confounding in Studies of the Effect of Maternal Drug Use on Pregnancy Outcome

PubMed Central

Källén, Bengt

2012-01-01

In most epidemilogical studies, the problem of confounding adds to the uncertainty in conclusions drawn. This is also true for studies on the effect of maternal drug use on birth defect risks. This paper describes various types of such confounders and discusses methods to identify and adjust for them. Such confounders can be found in maternal characteristics like age, parity, smoking, use of alcohol, and body mass index, subfertility, and previous pregnancies including previous birth of a malformed child, socioeconomy, race/ethnicity, or country of birth. Confounding by concomitant maternal drug use may occur. A geographical or seasonal confounding can exist. In rare instances, infant sex and multiple birth can appear as confounders. The most difficult problem to solve is often confounding by indication. The problem of confounding is less important for congenital malformations than for many other pregnancy outcomes. PMID:22190949

Susceptibility to price discounting of soda by neighbourhood educational status: an ecological analysis of disparities in soda consumption using point-of-purchase transaction data in Montreal, Canada.

PubMed

Mamiya, Hiroshi; Moodie, Erica E M; Ma, Yu; Buckeridge, David L

2018-06-22

Price discounting is a marketing tactic used frequently by food industries and retailers, but the extent to which education modifies the effect of discounting on the purchasing of unhealthy foods has received little attention. We investigated whether there was a differential association of price discounting of soda with store-level soda purchasing records between 2008 and 2013 by store-neighbourhood education in Montreal, Canada. Using data on grocery purchase transactions from a sample of supermarkets, pharmacies, supercentres and convenience stores, we performed an ecological time-series analysis, modelling weekly store-level sales of soda as a function of store-level price discounting, store- and neighbourhood-level confounders and an interaction term between discounting and categorical education in the neighbourhood of each store. Analysis by store type (n = 18 743, 12 437, 3965 and 49 533 store-weeks for superstores, pharmacies, supercentres and convenience stores, respectively) revealed that the effect measure modification of discounting by neighbourhood education on soda purchasing was lower in stores in the more educated neighbourhoods, most notably in pharmacies: -0.020 [95% confidence interval (CI): -0.028, -0.012] and -0.038 (95% CI: -0.051, -0.025), for middle- and high-education categories, respectively). Weaker effect modification was observed in convenience stores. There was no evidence of effect modification in supercentres or superstores. Price discounting is an important environmental risk factor for soda purchasing and can widen education inequalities in excess sugar intake across levels of education. Interventions to regulate price discounting warrant further investigation as a public health strategy to improve population nutrition, particularly in lower-education neighbourhoods.

Sensitivity analysis for direct and indirect effects in the presence of exposure-induced mediator-outcome confounders

PubMed Central

Chiba, Yasutaka

2014-01-01

Questions of mediation are often of interest in reasoning about mechanisms, and methods have been developed to address these questions. However, these methods make strong assumptions about the absence of confounding. Even if exposure is randomized, there may be mediator-outcome confounding variables. Inference about direct and indirect effects is particularly challenging if these mediator-outcome confounders are affected by the exposure because in this case these effects are not identified irrespective of whether data is available on these exposure-induced mediator-outcome confounders. In this paper, we provide a sensitivity analysis technique for natural direct and indirect effects that is applicable even if there are mediator-outcome confounders affected by the exposure. We give techniques for both the difference and risk ratio scales and compare the technique to other possible approaches. PMID:25580387

Assessment of Confounders in Comparative Effectiveness Studies From Secondary Databases.

PubMed

Franklin, Jessica M; Schneeweiss, Sebastian; Solomon, Daniel H

2017-03-15

Secondary clinical databases are an important and growing source of data for comparative effectiveness research (CER) studies. However, measurement of confounders, such as biomarker values or patient-reported health status, in secondary clinical databases may not align with the initiation of a new treatment. In many published CER analyses of registry data, investigators assessed confounders based on the first questionnaire in which the new exposure was recorded. However, it is known that adjustment for confounders measured after the start of exposure can lead to biased treatment effect estimates. In the present study, we conducted simulations to compare assessment strategies for a dynamic clinical confounder in a registry-based comparative effectiveness study of 2 therapies. As expected, we found that adjustment for the confounder value at the time of the first questionnaire after the start of exposure creates a biased estimate the total effect of exposure choice on outcome when the confounder mediates part of the effect. However, adjustment for the prior value can also be badly biased when measured long before exposure initiation. Thus, investigators should carefully consider the timing of confounder measurements relative to exposure initiation and the rate of change in the confounder in order to choose the most relevant measure for each patient. © The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Desert dust outbreaks and respiratory morbidity in Athens, Greece.

PubMed

Trianti, Stavroula-Myrto; Samoli, Evangelia; Rodopoulou, Sophia; Katsouyanni, Klea; Papiris, Spyros A; Karakatsani, Anna

2017-07-01

Ambient particulate matter (PM) has an adverse effect on respiratory morbidity. Desert dust outbreaks contribute to increased PM levels but the toxicity of desert dust mixed with anthropogenic pollutants needs clarification. We identified 132 days with desert dust episodes and 177 matched days by day of the week, season, temperature and humidity between 2001 and 2006 in Athens, Greece. We collected data on regulated pollutants and daily emergency outpatient visits and admissions for respiratory causes. We applied Poisson regression models adjusting for confounding effects of seasonality, meteorology, holidays and influenza epidemics. We evaluated the sensitivity of our results to co-pollutant exposures and effect modification by age and sex. A 10 μg/m 3 increase in PM 10 concentration was associated with 1.95% (95% confidence interval (CI): 0.02%, 3.91%) increase in respiratory emergency room visits. No significant interaction with desert dust episodes was observed. Compared with non-dust days, there was a 47% (95% CI: 29%, 68%) increase in visits in dust days not adjusting for PM 10 . Desert dust days were associated with higher numbers of emergency room visits for asthma, chronic obstructive pulmonary disease and respiratory infections with increases of 38%, 57% and 60%, respectively (p < 0.001 for all comparisons). Analyses of respiratory hospital admissions provided similar results. PM 10 effects decreased when adjusting for desert dust days and were further confounded by co-pollutants. Desert dust episode days are associated with higher respiratory emergency room visits and hospital admissions. This effect is insufficiently explained by increased PM 10 levels.

Is protective equipment useful in preventing concussion? A systematic review of the literature.

PubMed

Benson, B W; Hamilton, G M; Meeuwisse, W H; McCrory, P; Dvorak, J

2009-05-01

To determine if there is evidence that equipment use reduces sport concussion risk and/or severity. 12 electronic databases were searched using a combination of Medical Subject Headings and text words to identify relevant articles. Specific inclusion and exclusion criteria were used to select studies for review. Data extracted included design, study population, exposure/outcome measures and results. The quality of evidence was assessed based on epidemiologic criteria regarding internal and external validity (ie, strength of design, sample size/power calculation, selection bias, misclassification bias, control of potential confounding and effect modification). In total, 51 studies were selected for review. A comparison between studies was difficult due to the variability in research designs, definition of concussion, mouthguard/helmet/headgear/face shield types, measurements used to assess exposure and outcomes, and variety of sports assessed. The majority of studies were observational, with 23 analytical epidemiologic designs related to the subject area. Selection bias was a concern in the reviewed studies, as was the lack of measurement and control for potentially confounding variables. There is evidence that helmet use reduces head injury risk in skiing, snowboarding and bicycling, but the effect on concussion risk is inconclusive. No strong evidence exists for the use of mouthguards or face shields to reduce concussion risk. Evidence is provided to suggest that full facial protection in ice hockey may reduce concussion severity, as measured by time loss from competition.

Seasonal and temperature modifications of the association between fine particulate air pollution and cardiovascular hospitalization in New York state.

PubMed

Hsu, Wan-Hsiang; Hwang, Syni-An; Kinney, Patrick L; Lin, Shao

2017-02-01

It is known that extreme temperature and ambient air pollution are each independently associated with human health outcomes. However, findings from the few studies that have examined modified effects by seasons and the interaction between air pollution and temperature on health endpoints are inconsistent. This study examines the effects of short-term PM 2.5 (particulate matter less than or equal to 2.5μm in aerodynamic diameter) on hospitalization for cardiovascular diseases (CVDs), its modifications by season and temperature, and whether these effects are heterogeneous across different regions in New York State (NYS). We used daily average temperature and PM 2.5 concentrations as exposure indicators and performed a time series analysis with a quasi-Poisson model, controlling for possible confounders, such as time-relevant variables and dew point, for CVDs in NYS, 1991-2006. Stratification parametric models were applied to evaluate the modifying effects by seasons and temperature. Across the whole year, a 10-μg/m 3 increment in PM 2.5 concentration accounted for a 1.37% increase in CVDs (95% confidence interval (CI): 0.90%, 1.84%) in New York City, Long Island & Hudson. The PM 2.5 effect was strongest in winter, with an additional 2.06% (95% CI: 1.33%, 2.80%) increase in CVDs observed per 10-μg/m 3 increment in PM 2.5 . Temperature modified the PM 2.5 effects on CVDs, and these modifications by temperature on PM 2.5 effects on CVDs were found at low temperature days. These associations were heterogeneous across four PM 2.5 concentration regions. PM 2.5 was positively associated with CVD hospitalizations. The short-term PM 2.5 effect varied with season and temperature levels, and stronger effects were observed in winter and at low temperature days. Copyright © 2016 Elsevier B.V. All rights reserved.

Assessing Omitted Confounder Bias in Multilevel Mediation Models.

PubMed

Tofighi, Davood; Kelley, Ken

2016-01-01

To draw valid inference about an indirect effect in a mediation model, there must be no omitted confounders. No omitted confounders means that there are no common causes of hypothesized causal relationships. When the no-omitted-confounder assumption is violated, inference about indirect effects can be severely biased and the results potentially misleading. Despite the increasing attention to address confounder bias in single-level mediation, this topic has received little attention in the growing area of multilevel mediation analysis. A formidable challenge is that the no-omitted-confounder assumption is untestable. To address this challenge, we first analytically examined the biasing effects of potential violations of this critical assumption in a two-level mediation model with random intercepts and slopes, in which all the variables are measured at Level 1. Our analytic results show that omitting a Level 1 confounder can yield misleading results about key quantities of interest, such as Level 1 and Level 2 indirect effects. Second, we proposed a sensitivity analysis technique to assess the extent to which potential violation of the no-omitted-confounder assumption might invalidate or alter the conclusions about the indirect effects observed. We illustrated the methods using an empirical study and provided computer code so that researchers can implement the methods discussed.

Epidemiologic methods in clinical trials.

PubMed

Rothman, K J

1977-04-01

Epidemiologic methods developed to control confounding in non-experimental studies are equally applicable for experiments. In experiments, most confounding is usually controlled by random allocation of subjects to treatment groups, but randomization does not preclude confounding except for extremely large studies, the degree of confounding expected being inversely related to the size of the treatment groups. In experiments, as in non-experimental studies, the extent of confounding for each risk indicator should be assessed, and if sufficiently large, controlled. Confounding is properly assessed by comparing the unconfounded effect estimate to the crude effect estimate; a common error is to assess confounding by statistical tests of significance. Assessment of confounding involves its control as a prerequisite. Control is most readily and cogently achieved by stratification of the data, though with many factors to control simultaneously, multivariate analysis or a combination of multivariate analysis and stratification might be necessary.

Cardiovascular health, traffic-related air pollution and noise: are associations mutually confounded? A systematic review.

PubMed

Tétreault, Louis-François; Perron, Stéphane; Smargiassi, Audrey

2013-10-01

This review assessed the confounding effect of one traffic-related exposure (noise or air pollutants) on the association between the other exposure and cardiovascular outcomes. A systematic review was conducted with the databases Medline and Embase. The confounding effects in studies were assessed by using change in the estimate with a 10 % cutoff point. The influence on the change in the estimate of the quality of the studies, the exposure assessment methods and the correlation between road noise and air pollutions were also assessed. Nine publications were identified. For most studies, the specified confounders produced changes in estimates <10 %. The correlation between noise and pollutants, the quality of the study and of the exposure assessment do not seem to influence the confounding effects. Results from this review suggest that confounding of cardiovascular effects by noise or air pollutants is low, though with further improvements in exposure assessment, the situation may change. More studies using pollution indicators specific to road traffic are needed to properly assess if noise and air pollution are subjected to confounding.

Evaluation of uncontrolled confounding in studies of environmental exposures and neurobehavioral testing in children.

PubMed

Mink, Pamela J; Goodman, Michael; Barraj, Leila M; Imrey, Harriet; Kelsh, Michael A; Yager, Janice

2004-07-01

Neurobehavioral tests are commonly used in studies of children exposed to low-level environmental concentrations of compounds known to be neurotoxic at higher levels. However, uncontrolled or incomplete control for confounding makes interpretation of results problematic because effects of confounders are often stronger than the effects of primary interest. We examined a priori the potential impact of confounding in a hypothetical study evaluating the association of a potentially neurotoxic environmental exposure with neurobehavioral function in children. We used 2 outcome measures: the Bayley Scales of Infant Development Mental Development Index and the Stanford-Binet Intelligence Scale Composite Score. We selected 3 potential confounders: maternal intelligence, home environment, and socioeconomic status as measured by years of parental education. We conducted 3 sets of analyses measuring the effect of each of the 3 confounding factors alone, 2 confounders acting simultaneously, and all 3 confounders acting simultaneously. Relatively small differences (0.5 standard deviations) in confounding variables between "exposed" and "unexposed" groups, if unmeasured and unaccounted for in the analysis, could produce spurious differences in cognitive test scores. The magnitude of this difference (3-10 points) has been suggested to have a meaningful impact in populations. The method of measuring confounders (eg, maternal intelligence) could also substantially affect the results. It is important to carefully consider the impact of potential confounders during the planning stages of an observational study. Study-to-study differences in neurobehavioral outcomes with similar environmental exposures could be partially explained by differences in the adjustment for confounding variables. Copyright 2004 Lippincott Williams and Wilkins

Genetic signatures of natural selection in response to air pollution in red spruce (Picea rubens, Pinaceae).

PubMed

Bashalkhanov, Stanislav; Eckert, Andrew J; Rajora, Om P

2013-12-01

One of the most important drivers of local adaptation for forest trees is climate. Coupled to these patterns, however, are human-induced disturbances through habitat modification and pollution. The confounded effects of climate and disturbance have rarely been investigated with regard to selective pressure on forest trees. Here, we have developed and used a population genetic approach to search for signals of selection within a set of 36 candidate genes chosen for their putative effects on adaptation to climate and human-induced air pollution within five populations of red spruce (Picea rubens Sarg.), distributed across its natural range and air pollution gradient in eastern North America. Specifically, we used FST outlier and environmental correlation analyses to highlight a set of seven single nucleotide polymorphisms (SNPs) that were overly correlated with climate and levels of sulphate pollution after correcting for the confounding effects of population history. Use of three age cohorts within each population allowed the effects of climate and pollution to be separated temporally, as climate-related SNPs (n = 7) showed the strongest signals in the oldest cohort, while pollution-related SNPs (n = 3) showed the strongest signals in the youngest cohorts. These results highlight the usefulness of population genetic scans for the identification of putatively nonneutral evolution within genomes of nonmodel forest tree species, but also highlight the need for the development and application of robust methodologies to deal with the inherent multivariate nature of the genetic and ecological data used in these types of analyses. © 2013 John Wiley & Sons Ltd.

Using Chromatin Immunoprecipitation in Toxicology: A Step-by-Step Guide to Increasing Efficiency, Reducing Variability, and Expanding Applications.

PubMed

McCullough, Shaun D; On, Doan M; Bowers, Emma C

2017-05-02

Histone modifications work in concert with DNA methylation to regulate cellular structure, function, and response to environmental stimuli. More than 130 unique histone modifications have been described to date, and chromatin immunoprecipitation (ChIP) allows for the exploration of their associations with the regulatory regions of target genes and other DNA/chromatin-associated proteins across the genome. Many variations of ChIP have been developed in the 30 years since its earliest version came into use, which makes it challenging for users to integrate the procedure into their research programs. Furthermore, the differences in ChIP protocols can confound efforts to increase reproducibility across studies. The streamlined ChIP procedure presented here can be readily applied to samples from a wide range of in vitro studies (cell lines and primary cells) and clinical samples (peripheral leukocytes) in toxicology. We also provide detailed guidance on the optimization of critical protocol parameters, such as chromatin fixation, fragmentation, and immunoprecipitation, to increase efficiency and improve reproducibility. Expanding toxicoepigenetic studies to more readily include histone modifications will facilitate a more comprehensive understanding of the role of the epigenome in environmental exposure effects and the integration of epigenetic data in mechanistic toxicology, adverse outcome pathways, and risk assessment. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

Heatwave and infants' hospital admissions under different heatwave definitions.

PubMed

Xu, Zhiwei; Crooks, James Lewis; Black, Deborah; Hu, Wenbiao; Tong, Shilu

2017-10-01

Data on the health impacts of heatwaves in infants are limited, and this study aimed to examine how heatwaves affect hospital admissions in infants. A quasi-Poisson generalized additive model was used to assess the effects of heatwaves on hospital admissions in infants from 1st January 2005 to 31st December 2015 in Brisbane, Australia, using a series of heatwave definitions after controlling for possible confounders. A case-only analysis was conducted to examine the possible modification effects of personal and community characteristics on the heatwaves effects on infants' hospital admissions. There was no significant increase in infants' hospital admissions when heatwave intensity was defined as mean temperature ≥90 th percentile or ≥95th percentile of the mean temperature across the study period. When heatwave intensity increased to ≥97th percentile, infants' hospital admissions increased significantly (RR: 1.05, 95% CI: 1.01, 1.10), and this increase raised with the increase of heatwave duration. No modification effect of gender, indigenous status, or Socio-Economic Indexes for Areas (SEIFA) level on heatwave effect was observed. Infants in Brisbane were sensitive to intense heatwaves, and future heat early warning system based on a local evidence-based heatwave definition is needed to protect infants from heatwave impacts. Community-based heatwave adaptation programs aiming at raising the awareness of the adverse health impacts of intense heatwaves among infants' caregivers may relieve the postnatal health care demand in infants. Copyright © 2017 Elsevier Ltd. All rights reserved.

Examining the role of unmeasured confounding in mediation analysis with genetic and genomic applications.

PubMed

Lutz, Sharon M; Thwing, Annie; Schmiege, Sarah; Kroehl, Miranda; Baker, Christopher D; Starling, Anne P; Hokanson, John E; Ghosh, Debashis

2017-07-19

In mediation analysis if unmeasured confounding is present, the estimates for the direct and mediated effects may be over or under estimated. Most methods for the sensitivity analysis of unmeasured confounding in mediation have focused on the mediator-outcome relationship. The Umediation R package enables the user to simulate unmeasured confounding of the exposure-mediator, exposure-outcome, and mediator-outcome relationships in order to see how the results of the mediation analysis would change in the presence of unmeasured confounding. We apply the Umediation package to the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) study to examine the role of unmeasured confounding due to population stratification on the effect of a single nucleotide polymorphism (SNP) in the CHRNA5/3/B4 locus on pulmonary function decline as mediated by cigarette smoking. Umediation is a flexible R package that examines the role of unmeasured confounding in mediation analysis allowing for normally distributed or Bernoulli distributed exposures, outcomes, mediators, measured confounders, and unmeasured confounders. Umediation also accommodates multiple measured confounders, multiple unmeasured confounders, and allows for a mediator-exposure interaction on the outcome. Umediation is available as an R package at https://github.com/SharonLutz/Umediation A tutorial on how to install and use the Umediation package is available in the Additional file 1.

Potential sources of bias in the use of Escherichia coli to measure waterborne diarrhoea risk in low-income settings.

PubMed

Ercumen, Ayse; Arnold, Benjamin F; Naser, Abu Mohd; Unicomb, Leanne; Colford, John M; Luby, Stephen P

2017-01-01

Escherichia coli is the standard water quality indicator for diarrhoea risk. Yet, the association between E. coli and diarrhoea is inconsistent across studies without a systematic assessment of methodological differences behind this variation. Most studies measure water quality cross-sectionally with diarrhoea, risking exposure misclassification and reverse causation. Studies use different recall windows for self-reported diarrhoea; longer periods increase potential outcome misclassification through misrecall. Control of confounding is inconsistent across studies. Additionally, diarrhoea measured in unblinded intervention trials can present courtesy bias. We utilised measurements from a randomised trial of water interventions in Bangladesh to assess how these factors affect the E. coli-diarrhoea association. We compared cross-sectional versus prospective measurements of water quality and diarrhoea, 2-versus 7-day symptom recall periods, estimates with and without controlling for confounding and using measurements from control versus intervention arms of the trial. In the control arm, 2-day diarrhoea prevalence, measured prospectively 1 month after water quality, significantly increased with log 10 E. coli (PR = 1.50, 1.02-2.20). This association weakened when we used 7-day recall (PR = 1.18, 0.88-1.57), cross-sectional measurements of E. coli and diarrhoea (PR = 1.11, 0.79-1.56) or did not control for confounding (PR = 1.20, 0.88-1.62). Including data from intervention arms led to less interpretable associations, potentially due to courtesy bias, effect modification and/or reverse causation. By systematically addressing potential sources of bias, our analysis demonstrates a clear relationship between E. coli in drinking water and diarrhoea, suggesting that the continued use of E. coli as an indicator of waterborne diarrhoea risk is justified. © 2016 John Wiley & Sons Ltd.

Alcohol Use at Time of Injury and Survival Following Traumatic Brain Injury: Results From the National Trauma Data Bank

PubMed Central

Chen, Chiung M.; Yi, Hsiao-Ye; Yoon, Young-Hee; Dong, Chuanhui

2012-01-01

Objective: Premised on biological evidence from animal research, recent clinical studies have, for the most part, concluded that elevated blood alcohol concentration levels are independently associated with higher survival or decreased mortality in patients with moderate to severe traumatic brain injury (TBI). This study aims to provide some counterevidence to this claim and to further future investigations. Method: Incident data were drawn from the largest U.S. trauma registry, the National Trauma Data Bank, for emergency department admission years 2002–2006. TBI was identified according to the National Trauma Data Bank’s definition using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), codes. To eliminate confounding, the exact matching method was used to match alcohol-positive with alcohol-negative incidents on sex, age, race/ethnicity, and facility. Logistic regression compared in-hospital mortality between 44,043 alcohol-positive and 59,817 matched alcohol-negative TBI incidents, with and without causes and intents of TBI and Injury Severity Score as covariates. A sensitivity analysis was performed within a subsample of isolated moderate to severe TBI incidents. Results: Alcohol use at the time of injury was found to be significantly associated with an increased risk for TBI. Including varied causes and intents of TBI and Injury Severity Score as potential confounders in the regression model explained away the statistical significance of the seemingly protective effect of alcohol against TBI mortality for all TBIs and for isolated moderate to severe TBIs. Conclusions: The null finding shows that the purported reduction in TBI mortality attributed to positive blood alcohol likely is attributable to residual confounding. Accordingly, the risk of TBI associated with alcohol use should not be overlooked. PMID:22630791

Alcohol use at time of injury and survival following traumatic brain injury: results from the National Trauma Data Bank.

PubMed

Chen, Chiung M; Yi, Hsiao-Ye; Yoon, Young-Hee; Dong, Chuanhui

2012-07-01

Premised on biological evidence from animal research, recent clinical studies have, for the most part, concluded that elevated blood alcohol concentration levels are independently associated with higher survival or decreased mortality in patients with moderate to severe traumatic brain injury (TBI). This study aims to provide some counterevidence to this claim and to further future investigations. Incident data were drawn from the largest U.S. trauma registry, the National Trauma Data Bank, for emergency department admission years 2002-2006. TBI was identified according to the National Trauma Data Bank's definition using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), codes. To eliminate confounding, the exact matching method was used to match alcohol-positive with alcohol-negative incidents on sex, age, race/ethnicity, and facility. Logistic regression compared in-hospital mortality between 44,043 alcohol-positive and 59,817 matched alcohol-negative TBI incidents, with and without causes and intents of TBI and Injury Severity Score as covariates. A sensitivity analysis was performed within a subsample of isolated moderate to severe TBI incidents. Alcohol use at the time of injury was found to be significantly associated with an increased risk for TBI. Including varied causes and intents of TBI and Injury Severity Score as potential confounders in the regression model explained away the statistical significance of the seemingly protective effect of alcohol against TBI mortality for all TBIs and for isolated moderate to severe TBIs. The null finding shows that the purported reduction in TBI mortality attributed to positive blood alcohol likely is attributable to residual confounding. Accordingly, the risk of TBI associated with alcohol use should not be overlooked.

Air pollution and heart rate variability: effect modification by chronic lead exposure.

PubMed

Park, Sung Kyun; O'Neill, Marie S; Vokonas, Pantel S; Sparrow, David; Wright, Robert O; Coull, Brent; Nie, Huiling; Hu, Howard; Schwartz, Joel

2008-01-01

Outdoor air pollution and lead exposure can disturb cardiac autonomic function, but the effects of both these exposures together have not been studied. We examined whether higher cumulative lead exposures, as measured by bone lead, modified cross-sectional associations between air pollution and heart rate variability among 384 elderly men from the Normative Aging Study. We used linear regression, controlling for clinical, demographic, and environmental covariates. We found graded, significant reductions in both high-frequency and low-frequency powers of heart rate variability in relation to ozone and sulfate across the quartiles of tibia lead. Interquartile range increases in ozone and sulfate were associated respectively, with 38% decrease (95% confidence interval = -54.6% to -14.9%) and 22% decrease (-40.4% to 1.6%) in high frequency, and 38% decrease (-51.9% to -20.4%) and 12% decrease (-28.6% to 9.3%) in low frequency, in the highest quartile of tibia lead after controlling for potential confounders. We observed similar but weaker effect modification by tibia lead adjusted for education and cumulative traffic (residuals of the regression of tibia lead on education and cumulative traffic). Patella lead modified only the ozone effect on heart rate variability. People with long-term exposure to higher levels of lead may be more sensitive to cardiac autonomic dysfunction on high air pollution days. Efforts to understand how environmental exposures affect the health of an aging population should consider both current levels of pollution and history of lead exposure as susceptibility factors.

Asthma and atopy in children born by caesarean section: effect modification by family history of allergies - a population based cross-sectional study.

PubMed

Kolokotroni, Ourania; Middleton, Nicos; Gavatha, Marina; Lamnisos, Demetris; Priftis, Kostas N; Yiallouros, Panayiotis K

2012-11-16

Studies on the association of birth by caesarean section (C/S) and allergies have produced conflicting findings. Furthermore, evidence on whether this association may differ in those at risk of atopy is limited. This study aims to investigate the association of mode of delivery with asthma and atopic sensitization and the extent to which any effect is modified by family history of allergies. Asthma outcomes were assessed cross-sectionally in 2216 children at age 8 on the basis of parents' responses to the ISAAC questionnaire whilst skin prick tests to eleven aeroallergens were also performed in a subgroup of 746 children. Adjusted odds ratios of asthma and atopy by mode of delivery were estimated in multivariable logistic models while evidence of effect modification was examined by introducing interaction terms in the models. After adjusting for potential confounders, children born by C/S appeared significantly more likely than those born vaginally to report ever wheezing (OR 1.36, 95% CI 1.07-1.71), asthma diagnosis (OR 1.41, 95% CI 1.09-1.83) and be atopic (OR 1.67, 95% CI 1.08-2.60). There was modest evidence that family history of allergies may modify the effect of C/S delivery on atopy (p for effect modification=0.06) but this was not the case for the asthma outcomes. Specifically, while more than a two-fold increase in the odds of being a topic was observed in children with a family history of allergies if born by C/S (OR 2.62, 95% CI 1.38-5.00), no association was observed in children without a family history of allergies (OR 1.16, 95% CI 0.64-2.11). Birth by C/S is associated with asthma and atopic sensitization in childhood. The association of C/S and atopy appears more pronounced in children with family history of allergies.

JIM-13-0560 R1: Propensity scores for confounder adjustment when assessing the effects of medical interventions using non-experimental study designs

PubMed Central

Stürmer, Til; Wyss, Richard; Glynn, Robert J.; Brookhart, M. Alan

2014-01-01

Treatment effects, especially when comparing two or more therapeutic alternatives as in comparative effectiveness research, are likely to be heterogeneous across age, gender, co-morbidities, and co-medications. Propensity scores (PSs), an alternative to multivariable outcome models to control for measured confounding, have specific advantages in the presence of heterogeneous treatment effects. Implementing PSs using matching or weighting allows us to estimate different overall treatment effects in differently defined populations. Heterogeneous treatment effects can also be due to unmeasured confounding concentrated in those treated contrary to prediction. Sensitivity analyses based on PSs can help to assess such unmeasured confounding. PSs should be considered a primary or secondary analytic strategy in non-experimental medical research, including pharmacoepidemiology and non-experimental comparative effectiveness research. PMID:24520806

Can statistic adjustment of OR minimize the potential confounding bias for meta-analysis of case-control study? A secondary data analysis.

PubMed

Liu, Tianyi; Nie, Xiaolu; Wu, Zehao; Zhang, Ying; Feng, Guoshuang; Cai, Siyu; Lv, Yaqi; Peng, Xiaoxia

2017-12-29

Different confounder adjustment strategies were used to estimate odds ratios (ORs) in case-control study, i.e. how many confounders original studies adjusted and what the variables are. This secondary data analysis is aimed to detect whether there are potential biases caused by difference of confounding factor adjustment strategies in case-control study, and whether such bias would impact the summary effect size of meta-analysis. We included all meta-analyses that focused on the association between breast cancer and passive smoking among non-smoking women, as well as each original case-control studies included in these meta-analyses. The relative deviations (RDs) of each original study were calculated to detect how magnitude the adjustment would impact the estimation of ORs, compared with crude ORs. At the same time, a scatter diagram was sketched to describe the distribution of adjusted ORs with different number of adjusted confounders. Substantial inconsistency existed in meta-analysis of case-control studies, which would influence the precision of the summary effect size. First, mixed unadjusted and adjusted ORs were used to combine individual OR in majority of meta-analysis. Second, original studies with different adjustment strategies of confounders were combined, i.e. the number of adjusted confounders and different factors being adjusted in each original study. Third, adjustment did not make the effect size of original studies trend to constringency, which suggested that model fitting might have failed to correct the systematic error caused by confounding. The heterogeneity of confounder adjustment strategies in case-control studies may lead to further bias for summary effect size in meta-analyses, especially for weak or medium associations so that the direction of causal inference would be even reversed. Therefore, further methodological researches are needed, referring to the assessment of confounder adjustment strategies, as well as how to take this kind of bias into consideration when drawing conclusion based on summary estimation of meta-analyses.

Breast milk and cognitive development—the role of confounders: a systematic review

PubMed Central

Walfisch, Asnat; Sermer, Corey; Cressman, Alex; Koren, Gideon

2013-01-01

Objectives The association between breastfeeding and child cognitive development is conflicted by studies reporting positive and null effects. This relationship may be confounded by factors associated with breastfeeding, specifically maternal socioeconomic class and IQ. Design Systematic review of the literature. Setting and participants Any prospective or retrospective study, in any language, evaluating the association between breastfeeding and cognitive development using a validated method in healthy term infants, children or adults, was included. Primary and secondary outcome measures Extracted data included the study design, target population and sample size, breastfeeding exposure, cognitive development assessment tool used and participants’ age, summary of the results prior to, and following, adjustment for confounders, and all confounders adjusted for. Study quality was assessed as well. Results 84 studies met our inclusion criteria (34 rated as high quality, 26 moderate and 24 low quality). Critical assessment of accepted studies revealed the following associations: 21 null, 28 positive, 18 null after adjusting for confounders and 17 positive—diminished after adjusting for confounders. Directionality of effect did not correlate with study quality; however, studies showing a decreased effect after multivariate analysis were of superior quality compared with other study groupings (14/17 high quality, 82%). Further, studies that showed null or diminished effect after multivariate analysis corrected for significantly more confounders (7.7±3.4) as compared with those that found no change following adjustment (5.6±4.5, p=0.04). The majority of included studies were carried out during childhood (75%) and set in high-income countries (85.5%). Conclusions Much of the reported effect of breastfeeding on child neurodevelopment is due to confounding. It is unlikely that additional work will change the current synthesis. Future studies should attempt to rigorously control for all important confounders. Alternatively, study designs using sibling cohorts discordant for breastfeeding may yield more robust conclusions. PMID:23975102

Robustness of meta-analyses in finding gene × environment interactions

PubMed Central

Shi, Gang; Nehorai, Arye

2017-01-01

Meta-analyses that synthesize statistical evidence across studies have become important analytical tools for genetic studies. Inspired by the success of genome-wide association studies of the genetic main effect, researchers are searching for gene × environment interactions. Confounders are routinely included in the genome-wide gene × environment interaction analysis as covariates; however, this does not control for any confounding effects on the results if covariate × environment interactions are present. We carried out simulation studies to evaluate the robustness to the covariate × environment confounder for meta-regression and joint meta-analysis, which are two commonly used meta-analysis methods for testing the gene × environment interaction or the genetic main effect and interaction jointly. Here we show that meta-regression is robust to the covariate × environment confounder while joint meta-analysis is subject to the confounding effect with inflated type I error rates. Given vast sample sizes employed in genome-wide gene × environment interaction studies, non-significant covariate × environment interactions at the study level could substantially elevate the type I error rate at the consortium level. When covariate × environment confounders are present, type I errors can be controlled in joint meta-analysis by including the covariate × environment terms in the analysis at the study level. Alternatively, meta-regression can be applied, which is robust to potential covariate × environment confounders. PMID:28362796

Confounding in statistical mediation analysis: What it is and how to address it.

PubMed

Valente, Matthew J; Pelham, William E; Smyth, Heather; MacKinnon, David P

2017-11-01

Psychology researchers are often interested in mechanisms underlying how randomized interventions affect outcomes such as substance use and mental health. Mediation analysis is a common statistical method for investigating psychological mechanisms that has benefited from exciting new methodological improvements over the last 2 decades. One of the most important new developments is methodology for estimating causal mediated effects using the potential outcomes framework for causal inference. Potential outcomes-based methods developed in epidemiology and statistics have important implications for understanding psychological mechanisms. We aim to provide a concise introduction to and illustration of these new methods and emphasize the importance of confounder adjustment. First, we review the traditional regression approach for estimating mediated effects. Second, we describe the potential outcomes framework. Third, we define what a confounder is and how the presence of a confounder can provide misleading evidence regarding mechanisms of interventions. Fourth, we describe experimental designs that can help rule out confounder bias. Fifth, we describe new statistical approaches to adjust for measured confounders of the mediator-outcome relation and sensitivity analyses to probe effects of unmeasured confounders on the mediated effect. All approaches are illustrated with application to a real counseling intervention dataset. Counseling psychologists interested in understanding the causal mechanisms of their interventions can benefit from incorporating the most up-to-date techniques into their mediation analyses. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

The alarming problems of confounding equivalence using logistic regression models in the perspective of causal diagrams.

PubMed

Yu, Yuanyuan; Li, Hongkai; Sun, Xiaoru; Su, Ping; Wang, Tingting; Liu, Yi; Yuan, Zhongshang; Liu, Yanxun; Xue, Fuzhong

2017-12-28

Confounders can produce spurious associations between exposure and outcome in observational studies. For majority of epidemiologists, adjusting for confounders using logistic regression model is their habitual method, though it has some problems in accuracy and precision. It is, therefore, important to highlight the problems of logistic regression and search the alternative method. Four causal diagram models were defined to summarize confounding equivalence. Both theoretical proofs and simulation studies were performed to verify whether conditioning on different confounding equivalence sets had the same bias-reducing potential and then to select the optimum adjusting strategy, in which logistic regression model and inverse probability weighting based marginal structural model (IPW-based-MSM) were compared. The "do-calculus" was used to calculate the true causal effect of exposure on outcome, then the bias and standard error were used to evaluate the performances of different strategies. Adjusting for different sets of confounding equivalence, as judged by identical Markov boundaries, produced different bias-reducing potential in the logistic regression model. For the sets satisfied G-admissibility, adjusting for the set including all the confounders reduced the equivalent bias to the one containing the parent nodes of the outcome, while the bias after adjusting for the parent nodes of exposure was not equivalent to them. In addition, all causal effect estimations through logistic regression were biased, although the estimation after adjusting for the parent nodes of exposure was nearest to the true causal effect. However, conditioning on different confounding equivalence sets had the same bias-reducing potential under IPW-based-MSM. Compared with logistic regression, the IPW-based-MSM could obtain unbiased causal effect estimation when the adjusted confounders satisfied G-admissibility and the optimal strategy was to adjust for the parent nodes of outcome, which obtained the highest precision. All adjustment strategies through logistic regression were biased for causal effect estimation, while IPW-based-MSM could always obtain unbiased estimation when the adjusted set satisfied G-admissibility. Thus, IPW-based-MSM was recommended to adjust for confounders set.

Validation sampling can reduce bias in health care database studies: an illustration using influenza vaccination effectiveness.

PubMed

Nelson, Jennifer Clark; Marsh, Tracey; Lumley, Thomas; Larson, Eric B; Jackson, Lisa A; Jackson, Michael L

2013-08-01

Estimates of treatment effectiveness in epidemiologic studies using large observational health care databases may be biased owing to inaccurate or incomplete information on important confounders. Study methods that collect and incorporate more comprehensive confounder data on a validation cohort may reduce confounding bias. We applied two such methods, namely imputation and reweighting, to Group Health administrative data (full sample) supplemented by more detailed confounder data from the Adult Changes in Thought study (validation sample). We used influenza vaccination effectiveness (with an unexposed comparator group) as an example and evaluated each method's ability to reduce bias using the control time period before influenza circulation. Both methods reduced, but did not completely eliminate, the bias compared with traditional effectiveness estimates that do not use the validation sample confounders. Although these results support the use of validation sampling methods to improve the accuracy of comparative effectiveness findings from health care database studies, they also illustrate that the success of such methods depends on many factors, including the ability to measure important confounders in a representative and large enough validation sample, the comparability of the full sample and validation sample, and the accuracy with which the data can be imputed or reweighted using the additional validation sample information. Copyright © 2013 Elsevier Inc. All rights reserved.

Validation sampling can reduce bias in healthcare database studies: an illustration using influenza vaccination effectiveness

PubMed Central

Nelson, Jennifer C.; Marsh, Tracey; Lumley, Thomas; Larson, Eric B.; Jackson, Lisa A.; Jackson, Michael

2014-01-01

Objective Estimates of treatment effectiveness in epidemiologic studies using large observational health care databases may be biased due to inaccurate or incomplete information on important confounders. Study methods that collect and incorporate more comprehensive confounder data on a validation cohort may reduce confounding bias. Study Design and Setting We applied two such methods, imputation and reweighting, to Group Health administrative data (full sample) supplemented by more detailed confounder data from the Adult Changes in Thought study (validation sample). We used influenza vaccination effectiveness (with an unexposed comparator group) as an example and evaluated each method’s ability to reduce bias using the control time period prior to influenza circulation. Results Both methods reduced, but did not completely eliminate, the bias compared with traditional effectiveness estimates that do not utilize the validation sample confounders. Conclusion Although these results support the use of validation sampling methods to improve the accuracy of comparative effectiveness findings from healthcare database studies, they also illustrate that the success of such methods depends on many factors, including the ability to measure important confounders in a representative and large enough validation sample, the comparability of the full sample and validation sample, and the accuracy with which data can be imputed or reweighted using the additional validation sample information. PMID:23849144

Modeling formalin fixation and histological processing with ribonuclease A: effects of ethanol dehydration on reversal of formaldehyde cross-links.

PubMed

Fowler, Carol B; O'Leary, Timothy J; Mason, Jeffrey T

2008-07-01

Understanding the chemistry of protein modification by formaldehyde fixation and subsequent tissue processing is central to developing improved methods for antigen retrieval in immunohistochemistry and for recovering proteins from formalin-fixed, paraffin-embedded (FFPE) tissues for proteomic analysis. Our initial studies of single proteins, such as bovine pancreatic ribonuclease A (RNase A), in 10% buffered formalin solution revealed that upon removal of excess formaldehyde, monomeric RNase A exhibiting normal immunoreactivity could be recovered by heating at 60 degrees C for 30 min at pH 4. We next studied tissue surrogates, which are gelatin-like plugs of fixed proteins that have sufficient physical integrity to be processed using normal tissue histology. Following histological processing, proteins could be extracted from the tissue surrogates by combining heat, detergent, and a protein denaturant. However, gel electrophoresis revealed that the surrogate extracts contained a mixture of monomeric and multimeric proteins. This suggested that during the subsequent steps of tissue processing protein-formaldehyde adducts undergo further modifications that are not observed in aqueous proteins. As a first step toward understanding these additional modifications we have performed a comparative evaluation of RNase A following fixation in buffered formaldehyde alone and after subsequent dehydration in 100% ethanol by combining gel electrophoresis, chemical modification, and circular dichroism spectroscopic studies. Our results reveal that ethanol-induced rearrangement of the conformation of fixed RNase A leads to protein aggregation through the formation of large geometrically compatible hydrophobic beta-sheets that are likely stabilized by formaldehyde cross-links, hydrogen bonds, and van der Waals interactions. It requires substantial energy to reverse the formaldehyde cross-links within these sheets and regenerate protein monomers free of formaldehyde modifications. Accordingly, the ethanol-dehydration step in tissue histology may be important in confounding the successful recovery of proteins from FFPE tissues for immunohistochemical and proteomic analysis.

Environmental confounding in gene-environment interaction studies.

PubMed

Vanderweele, Tyler J; Ko, Yi-An; Mukherjee, Bhramar

2013-07-01

We show that, in the presence of uncontrolled environmental confounding, joint tests for the presence of a main genetic effect and gene-environment interaction will be biased if the genetic and environmental factors are correlated, even if there is no effect of either the genetic factor or the environmental factor on the disease. When environmental confounding is ignored, such tests will in fact reject the joint null of no genetic effect with a probability that tends to 1 as the sample size increases. This problem with the joint test vanishes under gene-environment independence, but it still persists if estimating the gene-environment interaction parameter itself is of interest. Uncontrolled environmental confounding will bias estimates of gene-environment interaction parameters even under gene-environment independence, but it will not do so if the unmeasured confounding variable itself does not interact with the genetic factor. Under gene-environment independence, if the interaction parameter without controlling for the environmental confounder is nonzero, then there is gene-environment interaction either between the genetic factor and the environmental factor of interest or between the genetic factor and the unmeasured environmental confounder. We evaluate several recently proposed joint tests in a simulation study and discuss the implications of these results for the conduct of gene-environment interaction studies.

Addressing unmeasured confounding in comparative observational research.

PubMed

Zhang, Xiang; Faries, Douglas E; Li, Hu; Stamey, James D; Imbens, Guido W

2018-04-01

Observational pharmacoepidemiological studies can provide valuable information on the effectiveness or safety of interventions in the real world, but one major challenge is the existence of unmeasured confounder(s). While many analytical methods have been developed for dealing with this challenge, they appear under-utilized, perhaps due to the complexity and varied requirements for implementation. Thus, there is an unmet need to improve understanding the appropriate course of action to address unmeasured confounding under a variety of research scenarios. We implemented a stepwise search strategy to find articles discussing the assessment of unmeasured confounding in electronic literature databases. Identified publications were reviewed and characterized by the applicable research settings and information requirements required for implementing each method. We further used this information to develop a best practice recommendation to help guide the selection of appropriate analytical methods for assessing the potential impact of unmeasured confounding. Over 100 papers were reviewed, and 15 methods were identified. We used a flowchart to illustrate the best practice recommendation which was driven by 2 critical components: (1) availability of information on the unmeasured confounders; and (2) goals of the unmeasured confounding assessment. Key factors for implementation of each method were summarized in a checklist to provide further assistance to researchers for implementing these methods. When assessing comparative effectiveness or safety in observational research, the impact of unmeasured confounding should not be ignored. Instead, we suggest quantitatively evaluating the impact of unmeasured confounding and provided a best practice recommendation for selecting appropriate analytical methods. Copyright © 2018 John Wiley & Sons, Ltd.

Exposure to violence in childhood is associated with higher body mass index in adolescence.

PubMed

Gooding, Holly C; Milliren, Carly; Austin, S Bryn; Sheridan, Margaret A; McLaughlin, Katie A

2015-12-01

To determine whether different types of childhood adversity are associated with body mass index (BMI) in adolescence, we studied 147 adolescents aged 13-17 years, 41% of whom reported exposure to at least one adversity (maltreatment, abuse, peer victimization, or witness to community or domestic violence). We examined associations between adversity type and age- and sex-specific BMI z-scores using linear regression and overweight and obese status using logistic regression. We adjusted for potential socio-demographic, behavioral, and psychological confounders and tested for effect modification by gender. Adolescents with a history of sexual abuse, emotional abuse, or peer victimization did not have significantly different BMI z-scores than those without exposure (p>0.05 for all comparisons). BMI z-scores were higher in adolescents who had experienced physical abuse (β=0.50, 95% CI 0.12-0.91) or witnessed domestic violence (β=0.85, 95% CI 0.30-1.40). Participants who witnessed domestic violence had almost 6 times the odds of being overweight or obese (95% CI: 1.09-30.7), even after adjustment for potential confounders. No gender-by-adversity interactions were found. Exposure to violence in childhood is associated with higher adolescent BMI. This finding highlights the importance of screening for violence in pediatric practice and providing obesity prevention counseling for youth. Copyright © 2015 Elsevier Ltd. All rights reserved.

Epigenetic Regulation of Immunological Alterations Following Prenatal Exposure to Marijuana Cannabinoids and its Long Term Consequences in Offspring

PubMed Central

Zumbrun, Elizabeth E.; Sido, Jessica M.; Nagarkatti, Prakash S.

2015-01-01

Use of marijuana during pregnancy is fairly commonplace and can be expected increase in frequency as more states legalize its recreational use. The cannabinoids present in marijuana have been shown to be immunosuppressive, yet the effect of prenatal exposure to cannabinoids on the immune system of the developing fetus, its long term consequences during adult stage of life, and transgenerational effects have not been well characterized. Confounding factors such as coexisting drug use make the impact of cannabis use on progeny inherently difficult to study in a human population. Data from various animal models suggests that in utero exposure to cannabinoids results in profound T cell dysfunction and a greatly reduced immune response to viral antigens. Furthermore, evidence from animal studies indicates that the immunosuppressive effects of cannabinoids can be mediated through epigenetic mechanisms such as altered microRNA, DNA methylation and histone modification profiles. Such studies support the hypothesis that that parental or prenatal exposure to cannabis can trigger epigenetic changes that could have significant immunological consequences for offspring as well as long term transgenerational effects. PMID:25618446

Which Propensity Score Method Best Reduces Confounder Imbalance? An Example From a Retrospective Evaluation of a Childhood Obesity Intervention.

PubMed

Schroeder, Krista; Jia, Haomiao; Smaldone, Arlene

Propensity score (PS) methods are increasingly being employed by researchers to reduce bias arising from confounder imbalance when using observational data to examine intervention effects. The purpose of this study was to examine PS theory and methodology and compare application of three PS methods (matching, stratification, weighting) to determine which best improves confounder balance. Baseline characteristics of a sample of 20,518 school-aged children with severe obesity (of whom 1,054 received an obesity intervention) were assessed prior to PS application. Three PS methods were then applied to the data to determine which showed the greatest improvement in confounder balance between the intervention and control group. The effect of each PS method on the outcome variable-body mass index percentile change at one year-was also examined. SAS 9.4 and Comprehensive Meta-analysis statistical software were used for analyses. Prior to PS adjustment, the intervention and control groups differed significantly on seven of 11 potential confounders. PS matching removed all differences. PS stratification and weighting both removed one difference but created two new differences. Sensitivity analyses did not change these results. Body mass index percentile at 1 year decreased in both groups. The size of the decrease was smaller in the intervention group, and the estimate of the decrease varied by PS method. Selection of a PS method should be guided by insight from statistical theory and simulation experiments, in addition to observed improvement in confounder balance. For this data set, PS matching worked best to correct confounder imbalance. Because each method varied in correcting confounder imbalance, we recommend that multiple PS methods be compared for ability to improve confounder balance before implementation in evaluating treatment effects in observational data.

Comparison of Statistical Approaches Dealing with Time-dependent Confounding in Drug Effectiveness Studies

PubMed Central

Karim, Mohammad Ehsanul; Petkau, John; Gustafson, Paul; Platt, Robert W.; Tremlett, Helen

2017-01-01

In longitudinal studies, if the time-dependent covariates are affected by the past treatment, time-dependent confounding may be present. For a time-to-event response, marginal structural Cox models (MSCMs) are frequently used to deal with such confounding. To avoid some of the problems of fitting MSCM, the sequential Cox approach has been suggested as an alternative. Although the estimation mechanisms are different, both approaches claim to estimate the causal effect of treatment by appropriately adjusting for time-dependent confounding. We carry out simulation studies to assess the suitability of the sequential Cox approach for analyzing time-to-event data in the presence of a time-dependent covariate that may or may not be a time-dependent confounder. Results from these simulations revealed that the sequential Cox approach is not as effective as MSCM in addressing the time-dependent confounding. The sequential Cox approach was also found to be inadequate in the presence of a time-dependent covariate. We propose a modified version of the sequential Cox approach that correctly estimates the treatment effect in both of the above scenarios. All approaches are applied to investigate the impact of beta-interferon treatment in delaying disability progression in the British Columbia Multiple Sclerosis cohort (1995 – 2008). PMID:27659168

Comparison of statistical approaches dealing with time-dependent confounding in drug effectiveness studies.

PubMed

Karim, Mohammad Ehsanul; Petkau, John; Gustafson, Paul; Platt, Robert W; Tremlett, Helen

2018-06-01

In longitudinal studies, if the time-dependent covariates are affected by the past treatment, time-dependent confounding may be present. For a time-to-event response, marginal structural Cox models are frequently used to deal with such confounding. To avoid some of the problems of fitting marginal structural Cox model, the sequential Cox approach has been suggested as an alternative. Although the estimation mechanisms are different, both approaches claim to estimate the causal effect of treatment by appropriately adjusting for time-dependent confounding. We carry out simulation studies to assess the suitability of the sequential Cox approach for analyzing time-to-event data in the presence of a time-dependent covariate that may or may not be a time-dependent confounder. Results from these simulations revealed that the sequential Cox approach is not as effective as marginal structural Cox model in addressing the time-dependent confounding. The sequential Cox approach was also found to be inadequate in the presence of a time-dependent covariate. We propose a modified version of the sequential Cox approach that correctly estimates the treatment effect in both of the above scenarios. All approaches are applied to investigate the impact of beta-interferon treatment in delaying disability progression in the British Columbia Multiple Sclerosis cohort (1995-2008).

Nonlinear Predictive Models for Multiple Mediation Analysis: With an Application to Explore Ethnic Disparities in Anxiety and Depression Among Cancer Survivors.

PubMed

Yu, Qingzhao; Medeiros, Kaelen L; Wu, Xiaocheng; Jensen, Roxanne E

2018-04-02

Mediation analysis allows the examination of effects of a third variable (mediator/confounder) in the causal pathway between an exposure and an outcome. The general multiple mediation analysis method (MMA), proposed by Yu et al., improves traditional methods (e.g., estimation of natural and controlled direct effects) to enable consideration of multiple mediators/confounders simultaneously and the use of linear and nonlinear predictive models for estimating mediation/confounding effects. Previous studies find that compared with non-Hispanic cancer survivors, Hispanic survivors are more likely to endure anxiety and depression after cancer diagnoses. In this paper, we applied MMA on MY-Health study to identify mediators/confounders and quantify the indirect effect of each identified mediator/confounder in explaining ethnic disparities in anxiety and depression among cancer survivors who enrolled in the study. We considered a number of socio-demographic variables, tumor characteristics, and treatment factors as potential mediators/confounders and found that most of the ethnic differences in anxiety or depression between Hispanic and non-Hispanic white cancer survivors were explained by younger diagnosis age, lower education level, lower proportions of employment, less likely of being born in the USA, less insurance, and less social support among Hispanic patients.

On the definition of a confounder

PubMed Central

VanderWeele, Tyler J.; Shpitser, Ilya

2014-01-01

Summary The causal inference literature has provided a clear formal definition of confounding expressed in terms of counterfactual independence. The causal inference literature has not, however, produced a clear formal definition of a confounder, as it has given priority to the concept of confounding over that of a confounder. We consider a number of candidate definitions arising from various more informal statements made in the literature. We consider the properties satisfied by each candidate definition, principally focusing on (i) whether under the candidate definition control for all “confounders” suffices to control for “confounding” and (ii) whether each confounder in some context helps eliminate or reduce confounding bias. Several of the candidate definitions do not have these two properties. Only one candidate definition of those considered satisfies both properties. We propose that a “confounder” be defined as a pre-exposure covariate C for which there exists a set of other covariates X such that effect of the exposure on the outcome is unconfounded conditional on (X, C) but such that for no proper subset of (X, C) is the effect of the exposure on the outcome unconfounded given the subset. A variable that helps reduce bias but not eliminate bias we propose referring to as a “surrogate confounder.” PMID:25544784

The causal effect of red blood cell folate on genome-wide methylation in cord blood: a Mendelian randomization approach.

PubMed

Binder, Alexandra M; Michels, Karin B

2013-12-04

Investigation of the biological mechanism by which folate acts to affect fetal development can inform appraisal of expected benefits and risk management. This research is ethically imperative given the ubiquity of folic acid fortified products in the US. Considering that folate is an essential component in the one-carbon metabolism pathway that provides methyl groups for DNA methylation, epigenetic modifications provide a putative molecular mechanism mediating the effect of folic acid supplementation on neonatal and pediatric outcomes. In this study we use a Mendelian Randomization Unnecessary approach to assess the effect of red blood cell (RBC) folate on genome-wide DNA methylation in cord blood. Site-specific CpG methylation within the proximal promoter regions of approximately 14,500 genes was analyzed using the Illumina Infinium Human Methylation27 Bead Chip for 50 infants from the Epigenetic Birth Cohort at Brigham and Women's Hospital in Boston. Using methylenetetrahydrofolate reductase genotype as the instrument, the Mendelian Randomization approach identified 7 CpG loci with a significant (mostly positive) association between RBC folate and methylation level. Among the genes in closest proximity to this significant subset of CpG loci, several enriched biologic processes were involved in nucleic acid transport and metabolic processing. Compared to the standard ordinary least squares regression method, our estimates were demonstrated to be more robust to unmeasured confounding. To the authors' knowledge, this is the largest genome-wide analysis of the effects of folate on methylation pattern, and the first to employ Mendelian Randomization to assess the effects of an exposure on epigenetic modifications. These results can help guide future analyses of the causal effects of periconceptional folate levels on candidate pathways.

Structural confounding of area-level deprivation and segreation: an empirical example

EPA Science Inventory

The neighborhood effects literature has grown, but its utility is limited by the lack of attention paid to non-random selection into neighborhoods. Confounding occurs when an exposure and an outcome share an underlying common cause. Confounding resulting from differential allocat...

Statistical primer: propensity score matching and its alternatives.

PubMed

Benedetto, Umberto; Head, Stuart J; Angelini, Gianni D; Blackstone, Eugene H

2018-06-01

Propensity score (PS) methods offer certain advantages over more traditional regression methods to control for confounding by indication in observational studies. Although multivariable regression models adjust for confounders by modelling the relationship between covariates and outcome, the PS methods estimate the treatment effect by modelling the relationship between confounders and treatment assignment. Therefore, methods based on the PS are not limited by the number of events, and their use may be warranted when the number of confounders is large, or the number of outcomes is small. The PS is the probability for a subject to receive a treatment conditional on a set of baseline characteristics (confounders). The PS is commonly estimated using logistic regression, and it is used to match patients with similar distribution of confounders so that difference in outcomes gives unbiased estimate of treatment effect. This review summarizes basic concepts of the PS matching and provides guidance in implementing matching and other methods based on the PS, such as stratification, weighting and covariate adjustment.

An introduction to instrumental variables analysis: part 1.

PubMed

Bennett, Derrick A

2010-01-01

There are several examples in the medical literature where the associations of treatment effects predicted by observational studies have been refuted by evidence from subsequent large-scale randomised trials. This is because of the fact that non-experimental studies are subject to confounding - and confounding cannot be entirely eliminated even if all known confounders have been measured in the study as there may be unknown confounders. The aim of this 2-part methodological primer is to introduce an emerging methodology for estimating treatment effects using observational data in the absence of good randomised evidence known as the method of instrumental variables. Copyright © 2010 S. Karger AG, Basel.

Using instrumental variables to estimate a Cox's proportional hazards regression subject to additive confounding

PubMed Central

Tosteson, Tor D.; Morden, Nancy E.; Stukel, Therese A.; O'Malley, A. James

2014-01-01

The estimation of treatment effects is one of the primary goals of statistics in medicine. Estimation based on observational studies is subject to confounding. Statistical methods for controlling bias due to confounding include regression adjustment, propensity scores and inverse probability weighted estimators. These methods require that all confounders are recorded in the data. The method of instrumental variables (IVs) can eliminate bias in observational studies even in the absence of information on confounders. We propose a method for integrating IVs within the framework of Cox's proportional hazards model and demonstrate the conditions under which it recovers the causal effect of treatment. The methodology is based on the approximate orthogonality of an instrument with unobserved confounders among those at risk. We derive an estimator as the solution to an estimating equation that resembles the score equation of the partial likelihood in much the same way as the traditional IV estimator resembles the normal equations. To justify this IV estimator for a Cox model we perform simulations to evaluate its operating characteristics. Finally, we apply the estimator to an observational study of the effect of coronary catheterization on survival. PMID:25506259

Using instrumental variables to estimate a Cox's proportional hazards regression subject to additive confounding.

PubMed

MacKenzie, Todd A; Tosteson, Tor D; Morden, Nancy E; Stukel, Therese A; O'Malley, A James

2014-06-01

The estimation of treatment effects is one of the primary goals of statistics in medicine. Estimation based on observational studies is subject to confounding. Statistical methods for controlling bias due to confounding include regression adjustment, propensity scores and inverse probability weighted estimators. These methods require that all confounders are recorded in the data. The method of instrumental variables (IVs) can eliminate bias in observational studies even in the absence of information on confounders. We propose a method for integrating IVs within the framework of Cox's proportional hazards model and demonstrate the conditions under which it recovers the causal effect of treatment. The methodology is based on the approximate orthogonality of an instrument with unobserved confounders among those at risk. We derive an estimator as the solution to an estimating equation that resembles the score equation of the partial likelihood in much the same way as the traditional IV estimator resembles the normal equations. To justify this IV estimator for a Cox model we perform simulations to evaluate its operating characteristics. Finally, we apply the estimator to an observational study of the effect of coronary catheterization on survival.

Parenting Practices at 24 to 47 Months and IQ at Age 8: Effect-Measure Modification by Infant Temperament

PubMed Central

Chong, Shiau Yun; Chittleborough, Catherine R.; Gregory, Tess; Mittinty, Murthy N.; Lynch, John W.; Smithers, Lisa G.

2016-01-01

Cognitive development might be influenced by parenting practices and child temperament. We examined whether the associations between parental warmth, control and intelligence quotient (IQ) may be heightened among children in difficult temperament. Participants were from the Avon Longitudinal Study of Parents and Children (n = 7,044). Temperament at 6 months was measured using the Revised Infant Temperament Questionnaire and classified into ‘easy’ and ‘difficult’. Parental warmth and control was measured at 24 to 47 months and both were classified into 2 groups using latent class analyses. IQ was measured at 8 years using the Wechsler Intelligence Scale for Children and dichotomized (<85 and ≥85) for analyzing effect-measure modification by temperament. Linear regression adjusted for multiple confounders and temperament showed lower parental warmth was weakly associated with lower IQ score [β = -0.52 (95% CI 1.26, 0.21)], and higher parental control was associated with lower IQ score [β = -2.21 (-2.95, -1.48)]. Stratification by temperament showed no increased risk of having low IQ in temperamentally difficult children [risk ratio (RR) = 0.97 95% CI 0.65, 1.45)] but an increased risk among temperamentally easy children (RR = 1.12 95% CI 0.95, 1.32) when parental warmth was low. There was also no increased risk of having low IQ in temperamentally difficult children (RR = 1.02 95% CI 0.69, 1.53) but there was an increased risk among temperamentally easy children (RR = 1.30 95% CI 1.11, 1.53) when parental control was high. For both parental warmth and control, there was some evidence of negative effect-measure modification by temperament on the risk-difference scale and the risk-ratio scale. It may be more appropriate to provide parenting interventions as a universal program rather than targeting children with difficult temperament. PMID:27027637

A comparison of pre- and post-remediation water quality, Mineral Creek, Colorado

USGS Publications Warehouse

Runkel, R.L.; Bencala, K.E.; Kimball, B.A.; Walton-Day, K.; Verplanck, P.L.

2009-01-01

Pre- and post-remediation data sets are used herein to assess the effectiveness of remedial measures implemented in the headwaters of the Mineral Creek watershed, where contamination from hard rock mining has led to elevated metal concentrations and acidic pH. Collection of pre- and post-remediation data sets generally followed the synoptic mass balance approach, in which numerous stream and inflow locations are sampled for the constituents of interest and estimates of streamflow are determined by tracer dilution. The comparison of pre- and post-remediation data sets is confounded by hydrologic effects and the effects of temporal variation. Hydrologic effects arise due to the relatively wet conditions that preceded the collection of pre-remediation data, and the relatively dry conditions associated with the post-remediation data set. This difference leads to a dilution effect in the upper part of the study reach, where pre-remediation concentrations were diluted by rainfall, and a source area effect in the lower part of the study reach, where a smaller portion of the watershed may have been contributing constituent mass during the drier post-remediation period. A second confounding factor, temporal variability, violates the steady-state assumption that underlies the synoptic mass balance approach, leading to false identification of constituent sources and sinks. Despite these complications, remedial actions completed in the Mineral Creek headwaters appear to have led to improvements in stream water quality, as post-remediation profiles of instream load are consistently lower than the pre-remediation profiles over the entire study reach for six of the eight constituents considered (aluminium, arsenic, cadmium, copper, iron, and zinc). Concentrations of aluminium, cadmium, copper, lead, and zinc remain above chronic aquatic-life standards, however, and additional remedial actions may be needed. Future implementations of the synoptic mass balance approach should be preceded by an assessment of temporal variability, and modifications to the synoptic sampling protocol should be made if necessary.

Interpretational confounding is due to misspecification, not to type of indicator: comment on Howell, Breivik, and Wilcox (2007).

PubMed

Bollen, Kenneth A

2007-06-01

R. D. Howell, E. Breivik, and J. B. Wilcox (2007) have argued that causal (formative) indicators are inherently subject to interpretational confounding. That is, they have argued that using causal (formative) indicators leads the empirical meaning of a latent variable to be other than that assigned to it by a researcher. Their critique of causal (formative) indicators rests on several claims: (a) A latent variable exists apart from the model when there are effect (reflective) indicators but not when there are causal (formative) indicators, (b) causal (formative) indicators need not have the same consequences, (c) causal (formative) indicators are inherently subject to interpretational confounding, and (d) a researcher cannot detect interpretational confounding when using causal (formative) indicators. This article shows that each claim is false. Rather, interpretational confounding is more a problem of structural misspecification of a model combined with an underidentified model that leaves these misspecifications undetected. Interpretational confounding does not occur if the model is correctly specified whether a researcher has causal (formative) or effect (reflective) indicators. It is the validity of a model not the type of indicator that determines the potential for interpretational confounding. Copyright 2007 APA, all rights reserved.

A New Method for Partial Correction of Residual Confounding in Time-Series and Other Observational Studies.

PubMed

Flanders, W Dana; Strickland, Matthew J; Klein, Mitchel

2017-05-15

Methods exist to detect residual confounding in epidemiologic studies. One requires a negative control exposure with 2 key properties: 1) conditional independence of the negative control and the outcome (given modeled variables) absent confounding and other model misspecification, and 2) associations of the negative control with uncontrolled confounders and the outcome. We present a new method to partially correct for residual confounding: When confounding is present and our assumptions hold, we argue that estimators from models that include a negative control exposure with these 2 properties tend to be less biased than those from models without it. Using regression theory, we provide theoretical arguments that support our claims. In simulations, we empirically evaluated the approach using a time-series study of ozone effects on asthma emergency department visits. In simulations, effect estimators from models that included the negative control exposure (ozone concentrations 1 day after the emergency department visit) had slightly or modestly less residual confounding than those from models without it. Theory and simulations show that including the negative control can reduce residual confounding, if our assumptions hold. Our method differs from available methods because it uses a regression approach involving an exposure-based indicator rather than a negative control outcome to partially correct for confounding. © The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Flight Operations Analysis Tool

NASA Technical Reports Server (NTRS)

Easter, Robert; Herrell, Linda; Pomphrey, Richard; Chase, James; Wertz Chen, Julie; Smith, Jeffrey; Carter, Rebecca

2006-01-01

Flight Operations Analysis Tool (FLOAT) is a computer program that partly automates the process of assessing the benefits of planning spacecraft missions to incorporate various combinations of launch vehicles and payloads. Designed primarily for use by an experienced systems engineer, FLOAT makes it possible to perform a preliminary analysis of trade-offs and costs of a proposed mission in days, whereas previously, such an analysis typically lasted months. FLOAT surveys a variety of prior missions by querying data from authoritative NASA sources pertaining to 20 to 30 mission and interface parameters that define space missions. FLOAT provides automated, flexible means for comparing the parameters to determine compatibility or the lack thereof among payloads, spacecraft, and launch vehicles, and for displaying the results of such comparisons. Sparseness, typical of the data available for analysis, does not confound this software. FLOAT effects an iterative process that identifies modifications of parameters that could render compatible an otherwise incompatible mission set.

Results from using a new dyadic-dependence model to analyze sociocentric physician networks.

PubMed

Paul, Sudeshna; Keating, Nancy L; Landon, Bruce E; O'Malley, A James

2014-09-01

Professional physician networks can potentially influence clinical practices and quality of care. With the current focus on coordinated care, discerning influences of naturally occurring clusters and other forms of dependence among physicians' relationships based on their attributes and care patterns is an important area of research. In this paper, two directed physician networks: a physician influential conversation network (N = 33) and a physician network obtained from patient visit data (N = 135) are analyzed using a new model that accounts for effect modification of the within-dyad effect of reciprocity and inter-dyad effects involving three (or more) actors. The results from this model include more nuanced effects involving reciprocity and triadic dependence than under incumbent models and more flexible control for these effects in the extraction of other network phenomena, including the relationship between similarity of individuals' attributes (e.g., same-gender, same residency location) and tie-status. In both cases we find extensive evidence of clustering and triadic dependence that if not accounted for confounds the effect of reciprocity and attribute homophily. Findings from our analysis suggest alternative conclusions to those from incumbent models. Copyright © 2014 Elsevier Ltd. All rights reserved.

Does educational status impact adult mortality in Denmark? A twin approach.

PubMed

Madsen, Mia; Andersen, Anne-Marie Nybo; Christensen, Kaare; Andersen, Per Kragh; Osler, Merete

2010-07-15

To disentangle an independent effect of educational status on mortality risk from direct and indirect selection mechanisms, the authors used a discordant twin pair design, which allowed them to isolate the effect of education by means of adjustment for genetic and environmental confounding per design. The study is based on data from the Danish Twin Registry and Statistics Denmark. Using Cox regression, they estimated hazard ratios for mortality according to the highest attained education among 5,260 monozygotic and 11,088 dizygotic same-sex twin pairs born during 1921-1950 and followed during 1980-2008. Both standard cohort and intrapair analyses were conducted separately for zygosity, gender, and birth cohort. Educational differences in mortality were demonstrated in the standard cohort analyses but attenuated in the intrapair analyses in all subgroups but men born during 1921-1935, and no effect modification by zygosity was observed. Hence, the results are most compatible with an effect of early family environment in explaining the educational inequality in mortality. However, large educational differences were still reflected in mortality risk differences within twin pairs, thus supporting some degree of independent effect of education. In addition, the effect of education may be more pronounced in older cohorts of Danish men.

Semiparametric time varying coefficient model for matched case-crossover studies.

PubMed

Ortega-Villa, Ana Maria; Kim, Inyoung; Kim, H

2017-03-15

In matched case-crossover studies, it is generally accepted that the covariates on which a case and associated controls are matched cannot exert a confounding effect on independent predictors included in the conditional logistic regression model. This is because any stratum effect is removed by the conditioning on the fixed number of sets of the case and controls in the stratum. Hence, the conditional logistic regression model is not able to detect any effects associated with the matching covariates by stratum. However, some matching covariates such as time often play an important role as an effect modification leading to incorrect statistical estimation and prediction. Therefore, we propose three approaches to evaluate effect modification by time. The first is a parametric approach, the second is a semiparametric penalized approach, and the third is a semiparametric Bayesian approach. Our parametric approach is a two-stage method, which uses conditional logistic regression in the first stage and then estimates polynomial regression in the second stage. Our semiparametric penalized and Bayesian approaches are one-stage approaches developed by using regression splines. Our semiparametric one stage approach allows us to not only detect the parametric relationship between the predictor and binary outcomes, but also evaluate nonparametric relationships between the predictor and time. We demonstrate the advantage of our semiparametric one-stage approaches using both a simulation study and an epidemiological example of a 1-4 bi-directional case-crossover study of childhood aseptic meningitis with drinking water turbidity. We also provide statistical inference for the semiparametric Bayesian approach using Bayes Factors. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Heat and mortality for ischemic and hemorrhagic stroke in 12 cities of Jiangsu Province, China.

PubMed

Zhou, Lian; Chen, Kai; Chen, Xiaodong; Jing, Yuanshu; Ma, Zongwei; Bi, Jun; Kinney, Patrick L

2017-12-01

Little evidence exists on the relationship between heat and subtypes of stroke mortality, especially in China. Moreover, few studies have reported the effect modification by individual characteristics on heat-related stroke mortality. In this study, we aimed to evaluate the effect of heat exposure on total, ischemic, and hemorrhagic stroke mortality and its individual modifiers in 12 cities in Jiangsu Province, China during 2009 to 2013. We first used a distributed lag non-linear model with quasi-Poisson regression to examine the city-specific heat-related total, ischemic, and hemorrhagic stroke mortality risks at 99th percentile vs. 75th percentile of daily mean temperature in the whole year for each city, while adjusting for long-term trend, season, relative humidity, and day of the week. Then, we used a random-effects meta-analysis to pool the city-specific risk estimates. We also considered confounding by air pollution and effect modification by gender, age, education level, and death location. Overall, the heat-related mortality risk in 12 Jiangsu cities was 1.54 (95%CI: 1.44 to 1.65) for total stroke, 1.63 (95%CI: 1.48 to 1.80) for ischemic stroke, and 1.36 (95%CI: 1.26 to 1.48) for hemorrhagic stroke, respectively. Estimated total, ischemic, and hemorrhagic stroke mortality risks were higher for women versus men, older people versus younger people, those with low education levels versus high education levels, and deaths that occurred outside of hospital. Air pollutants did not significantly influence the heat-related stroke mortality risk. Heat exposure significantly increased both ischemic and hemorrhagic stroke mortality risks in Jiangsu Province, China. Females, the elderly, and those with low education levels are particularly vulnerable to this effect. Copyright © 2017 Elsevier B.V. All rights reserved.

Assessing mediation using marginal structural models in the presence of confounding and moderation

PubMed Central

Coffman, Donna L.; Zhong, Wei

2012-01-01

This paper presents marginal structural models (MSMs) with inverse propensity weighting (IPW) for assessing mediation. Generally, individuals are not randomly assigned to levels of the mediator. Therefore, confounders of the mediator and outcome may exist that limit causal inferences, a goal of mediation analysis. Either regression adjustment or IPW can be used to take confounding into account, but IPW has several advantages. Regression adjustment of even one confounder of the mediator and outcome that has been influenced by treatment results in biased estimates of the direct effect (i.e., the effect of treatment on the outcome that does not go through the mediator). One advantage of IPW is that it can properly adjust for this type of confounding, assuming there are no unmeasured confounders. Further, we illustrate that IPW estimation provides unbiased estimates of all effects when there is a baseline moderator variable that interacts with the treatment, when there is a baseline moderator variable that interacts with the mediator, and when the treatment interacts with the mediator. IPW estimation also provides unbiased estimates of all effects in the presence of non-randomized treatments. In addition, for testing mediation we propose a test of the null hypothesis of no mediation. Finally, we illustrate this approach with an empirical data set in which the mediator is continuous, as is often the case in psychological research. PMID:22905648

Assessing mediation using marginal structural models in the presence of confounding and moderation.

PubMed

Coffman, Donna L; Zhong, Wei

2012-12-01

This article presents marginal structural models with inverse propensity weighting (IPW) for assessing mediation. Generally, individuals are not randomly assigned to levels of the mediator. Therefore, confounders of the mediator and outcome may exist that limit causal inferences, a goal of mediation analysis. Either regression adjustment or IPW can be used to take confounding into account, but IPW has several advantages. Regression adjustment of even one confounder of the mediator and outcome that has been influenced by treatment results in biased estimates of the direct effect (i.e., the effect of treatment on the outcome that does not go through the mediator). One advantage of IPW is that it can properly adjust for this type of confounding, assuming there are no unmeasured confounders. Further, we illustrate that IPW estimation provides unbiased estimates of all effects when there is a baseline moderator variable that interacts with the treatment, when there is a baseline moderator variable that interacts with the mediator, and when the treatment interacts with the mediator. IPW estimation also provides unbiased estimates of all effects in the presence of nonrandomized treatments. In addition, for testing mediation we propose a test of the null hypothesis of no mediation. Finally, we illustrate this approach with an empirical data set in which the mediator is continuous, as is often the case in psychological research. PsycINFO Database Record (c) 2013 APA, all rights reserved.

Extreme ambient temperatures and cardiorespiratory emergency room visits: assessing risk by comorbid health conditions in a time series study

PubMed Central

2014-01-01

Background Extreme ambient temperatures are an increasing public health concern. The aim of this study was to assess if persons with comorbid health conditions were at increased risk of adverse cardiorespiratory morbidity during temperature extremes. Methods A time series study design was applied to 292,666 and 562,738 emergency room (ER) visits for cardiovascular and respiratory diseases, respectively, that occurred in Toronto area hospitals between April 1st 2002 and March 31st 2010. Subgroups of persons with comorbid health conditions were identified. Relative risks (RRs) and their corresponding 95% confidence intervals (CIs) were estimated using a Poisson regression model with distributed lag non-linear model, and were adjusted for the confounding influence of seasonality, relative humidity, day-of-the-week, outdoor air pollutants and daily influenza ER visits. Effect modification by comorbid health conditions was tested using the relative effect modification (REM) index. Results Stronger associations of cardiovascular disease ER visits were observed for persons with diabetes compared to persons without diabetes (REM = 1.12; 95% CI: 1.01 – 1.27) with exposure to the cumulative short term effect of extreme hot temperatures (i.e. 99th percentile of temperature distribution vs. 75th percentile). Effect modification was also found for comorbid respiratory disease (REM = 1.17; 95% CI: 1.02 – 1.44) and cancer (REM = 1.20; 95% CI: 1.02 – 1.49) on respiratory disease ER visits during short term hot temperature episodes. The effect of extreme cold temperatures (i.e. 1st percentile of temperature distribution vs. 25th percentile) on cardiovascular disease ER visits were stronger for individuals with comorbid cardiac diseases (REM = 1.47; 95% CI: 1.06 – 2.23) and kidney diseases (REM = 2.43; 95% CI: 1.59 – 8.83) compared to those without these conditions when cumulated over a two-week period. Conclusions The identification of those most susceptible to temperature extremes is important for public health officials to implement adaptation measures to manage the impact of extreme temperatures on population health. PMID:24484632

Past physical activity and age-related macular degeneration: the Melbourne Collaborative Cohort Study.

PubMed

McGuinness, Myra B; Karahalios, Amalia; Simpson, Julie A; Guymer, Robyn H; Robman, Luba D; Hodge, Allison M; Cerin, Ester; Giles, Graham G; Finger, Robert P

2016-10-01

To assess the association between past physical activity and early, intermediate and late age-related macular degeneration (AMD) in a community-based cohort study in Melbourne, Australia. Diet and lifestyle information was recorded at baseline (1990-1994) and total recreational activity was derived from walking, vigorous and non-vigorous exercise. At follow-up (2003-2007), digital macular photographs were graded for early, intermediate and late AMD. Data were analysed using multinomial logistic regression controlling for age, sex, smoking, region of descent, diet and alcohol. Effect modification by sex was investigated. Out of 20 816 participants, early, intermediate and late AMD were detected at follow-up in 4244 (21%), 2661 (13%) and 122 (0.6%) participants, respectively. No association was detected between past total recreational physical activity and early, intermediate or late AMD. Frequent (≥3 times/week) and less frequent (1-2 times/week) vigorous exercise were associated with lower odds of intermediate and late AMD in univariable models. After controlling for confounders, there was evidence of effect modification by sex and frequent vigorous exercise was associated with a 22% decrease in the odds of intermediate AMD (95% CI 4% to 36%) in women, but no association was found for men. Past frequent vigorous exercise may be inversely related to the presence of intermediate AMD in women. Further studies are needed to confirm whether physical activity and exercise have a protective effect for AMD. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Effect decomposition in the presence of an exposure-induced mediator-outcome confounder

PubMed Central

VanderWeele, Tyler J.; Vansteelandt, Stijn; Robins, James M.

2014-01-01

Methods from causal mediation analysis have generalized the traditional approach to direct and indirect effects in the epidemiologic and social science literature by allowing for interaction and non-linearities. However, the methods from the causal inference literature have themselves been subject to a major limitation in that the so-called natural direct and indirect effects that are employed are not identified from data whenever there is a variable that is affected by the exposure, which also confounds the relationship between the mediator and the outcome. In this paper we describe three alternative approaches to effect decomposition that give quantities that can be interpreted as direct and indirect effects, and that can be identified from data even in the presence of an exposure-induced mediator-outcome confounder. We describe a simple weighting-based estimation method for each of these three approaches, illustrated with data from perinatal epidemiology. The methods described here can shed insight into pathways and questions of mediation even when an exposure-induced mediator-outcome confounder is present. PMID:24487213

Prognostic significance of social network, social support and loneliness for course of major depressive disorder in adulthood and old age.

PubMed

van den Brink, R H S; Schutter, N; Hanssen, D J C; Elzinga, B M; Rabeling-Keus, I M; Stek, M L; Comijs, H C; Penninx, B W J H; Oude Voshaar, R C

2018-06-01

Poor recovery from depressive disorder has been shown to be related to low perceived social support and loneliness, but not to social network size or frequency of social interactions. Some studies suggest that the significance of social relationships for depression course may be greater in younger than in older patients, and may differ between men and women. None of the studies examined to what extent the different aspects of social relationships have unique or overlapping predictive values for depression course. It is the aim of the present study to examine the differential predictive values of social network characteristics, social support and loneliness for the course of depressive disorder, and to test whether these predictive associations are modified by gender or age. Two naturalistic cohort studies with the same design and overlapping instruments were combined to obtain a study sample of 1474 patients with a major depressive disorder, of whom 1181 (80.1%) could be studied over a 2-year period. Social relational variables were assessed at baseline. Two aspects of depression course were studied: remission at 2-year follow-up and change in depression severity over the follow-up period. By means of logistic regression and random coefficient analysis, the individual and combined predictive values of the different social relational variables for depression course were studied, controlling for potential confounders and checking for effect modification by age (below 60 v. 60 years or older) and gender. Multiple aspects of the social network, social support and loneliness were related to depression course, independent of potential confounders - including depression severity - but when combined, their predictive values were found to overlap to a large extent. Only the social network characteristic of living in a larger household, the social support characteristic of few negative experiences with the support from a partner or close friend, and limited feelings of loneliness proved to have unique predictive value for a favourable course of depression. Little evidence was found for effect modification by gender or age. If depressed persons experience difficulties in their social relationships, this may impede their recovery. Special attention for interpersonal problems, social isolation and feelings of loneliness seems warranted in depression treatment and relapse prevention. It will be of great interest to test whether social relational interventions can contribute to better recovery and relapse prevention of depressive disorder.

Evaluating Public Health Interventions: 3. The Two-Stage Design for Confounding Bias Reduction-Having Your Cake and Eating It Two.

PubMed

Spiegelman, Donna; Rivera-Rodriguez, Claudia L; Haneuse, Sebastien

2016-07-01

In public health evaluations, confounding bias in the estimate of the intervention effect will typically threaten the validity of the findings. It is a common misperception that the only way to avoid this bias is to measure detailed, high-quality data on potential confounders for every intervention participant, but this strategy for adjusting for confounding bias is often infeasible. Rather than ignoring confounding altogether, the two-phase design and analysis-in which detailed high-quality confounding data are obtained among a small subsample-can be considered. We describe the two-stage design and analysis approach, and illustrate its use in the evaluation of an intervention conducted in Dar es Salaam, Tanzania, of an enhanced community health worker program to improve antenatal care uptake.

Causal Methods for Observational Research: A Primer.

PubMed

Almasi-Hashiani, Amir; Nedjat, Saharnaz; Mansournia, Mohammad Ali

2018-04-01

The goal of many observational studies is to estimate the causal effect of an exposure on an outcome after adjustment for confounders, but there are still some serious errors in adjusting confounders in clinical journals. Standard regression modeling (e.g., ordinary logistic regression) fails to estimate the average effect of exposure in total population in the presence of interaction between exposure and covariates, and also cannot adjust for time-varying confounding appropriately. Moreover, stepwise algorithms of the selection of confounders based on P values may miss important confounders and lead to bias in effect estimates. Causal methods overcome these limitations. We illustrate three causal methods including inverse-probability-of-treatment-weighting (IPTW) and parametric g-formula, with an emphasis on a clever combination of these 2 methods: targeted maximum likelihood estimation (TMLE) which enjoys a double-robust property against bias. © 2018 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

More Precise Estimation of Lower-Level Interaction Effects in Multilevel Models.

PubMed

Loeys, Tom; Josephy, Haeike; Dewitte, Marieke

2018-01-01

In hierarchical data, the effect of a lower-level predictor on a lower-level outcome may often be confounded by an (un)measured upper-level factor. When such confounding is left unaddressed, the effect of the lower-level predictor is estimated with bias. Separating this effect into a within- and between-component removes such bias in a linear random intercept model under a specific set of assumptions for the confounder. When the effect of the lower-level predictor is additionally moderated by another lower-level predictor, an interaction between both lower-level predictors is included into the model. To address unmeasured upper-level confounding, this interaction term ought to be decomposed into a within- and between-component as well. This can be achieved by first multiplying both predictors and centering that product term next, or vice versa. We show that while both approaches, on average, yield the same estimates of the interaction effect in linear models, the former decomposition is much more precise and robust against misspecification of the effects of cross-level and upper-level terms, compared to the latter.

The Combined Effects of Measurement Error and Omitting Confounders in the Single-Mediator Model

PubMed Central

Fritz, Matthew S.; Kenny, David A.; MacKinnon, David P.

2016-01-01

Mediation analysis requires a number of strong assumptions be met in order to make valid causal inferences. Failing to account for violations of these assumptions, such as not modeling measurement error or omitting a common cause of the effects in the model, can bias the parameter estimates of the mediated effect. When the independent variable is perfectly reliable, for example when participants are randomly assigned to levels of treatment, measurement error in the mediator tends to underestimate the mediated effect, while the omission of a confounding variable of the mediator to outcome relation tends to overestimate the mediated effect. Violations of these two assumptions often co-occur, however, in which case the mediated effect could be overestimated, underestimated, or even, in very rare circumstances, unbiased. In order to explore the combined effect of measurement error and omitted confounders in the same model, the impact of each violation on the single-mediator model is first examined individually. Then the combined effect of having measurement error and omitted confounders in the same model is discussed. Throughout, an empirical example is provided to illustrate the effect of violating these assumptions on the mediated effect. PMID:27739903

Bayesian effect estimation accounting for adjustment uncertainty.

PubMed

Wang, Chi; Parmigiani, Giovanni; Dominici, Francesca

2012-09-01

Model-based estimation of the effect of an exposure on an outcome is generally sensitive to the choice of which confounding factors are included in the model. We propose a new approach, which we call Bayesian adjustment for confounding (BAC), to estimate the effect of an exposure of interest on the outcome, while accounting for the uncertainty in the choice of confounders. Our approach is based on specifying two models: (1) the outcome as a function of the exposure and the potential confounders (the outcome model); and (2) the exposure as a function of the potential confounders (the exposure model). We consider Bayesian variable selection on both models and link the two by introducing a dependence parameter, ω, denoting the prior odds of including a predictor in the outcome model, given that the same predictor is in the exposure model. In the absence of dependence (ω= 1), BAC reduces to traditional Bayesian model averaging (BMA). In simulation studies, we show that BAC, with ω > 1, estimates the exposure effect with smaller bias than traditional BMA, and improved coverage. We, then, compare BAC, a recent approach of Crainiceanu, Dominici, and Parmigiani (2008, Biometrika 95, 635-651), and traditional BMA in a time series data set of hospital admissions, air pollution levels, and weather variables in Nassau, NY for the period 1999-2005. Using each approach, we estimate the short-term effects of on emergency admissions for cardiovascular diseases, accounting for confounding. This application illustrates the potentially significant pitfalls of misusing variable selection methods in the context of adjustment uncertainty. © 2012, The International Biometric Society.

Estimating scaled treatment effects with multiple outcomes.

PubMed

Kennedy, Edward H; Kangovi, Shreya; Mitra, Nandita

2017-01-01

In classical study designs, the aim is often to learn about the effects of a treatment or intervention on a single outcome; in many modern studies, however, data on multiple outcomes are collected and it is of interest to explore effects on multiple outcomes simultaneously. Such designs can be particularly useful in patient-centered research, where different outcomes might be more or less important to different patients. In this paper, we propose scaled effect measures (via potential outcomes) that translate effects on multiple outcomes to a common scale, using mean-variance and median-interquartile range based standardizations. We present efficient, nonparametric, doubly robust methods for estimating these scaled effects (and weighted average summary measures), and for testing the null hypothesis that treatment affects all outcomes equally. We also discuss methods for exploring how treatment effects depend on covariates (i.e., effect modification). In addition to describing efficiency theory for our estimands and the asymptotic behavior of our estimators, we illustrate the methods in a simulation study and a data analysis. Importantly, and in contrast to much of the literature concerning effects on multiple outcomes, our methods are nonparametric and can be used not only in randomized trials to yield increased efficiency, but also in observational studies with high-dimensional covariates to reduce confounding bias.

Study design and statistical analysis of data in human population studies with the micronucleus assay.

PubMed

Ceppi, Marcello; Gallo, Fabio; Bonassi, Stefano

2011-01-01

The most common study design performed in population studies based on the micronucleus (MN) assay, is the cross-sectional study, which is largely performed to evaluate the DNA damaging effects of exposure to genotoxic agents in the workplace, in the environment, as well as from diet or lifestyle factors. Sample size is still a critical issue in the design of MN studies since most recent studies considering gene-environment interaction, often require a sample size of several hundred subjects, which is in many cases difficult to achieve. The control of confounding is another major threat to the validity of causal inference. The most popular confounders considered in population studies using MN are age, gender and smoking habit. Extensive attention is given to the assessment of effect modification, given the increasing inclusion of biomarkers of genetic susceptibility in the study design. Selected issues concerning the statistical treatment of data have been addressed in this mini-review, starting from data description, which is a critical step of statistical analysis, since it allows to detect possible errors in the dataset to be analysed and to check the validity of assumptions required for more complex analyses. Basic issues dealing with statistical analysis of biomarkers are extensively evaluated, including methods to explore the dose-response relationship among two continuous variables and inferential analysis. A critical approach to the use of parametric and non-parametric methods is presented, before addressing the issue of most suitable multivariate models to fit MN data. In the last decade, the quality of statistical analysis of MN data has certainly evolved, although even nowadays only a small number of studies apply the Poisson model, which is the most suitable method for the analysis of MN data.

Historic air pollution exposure and long-term mortality risks in England and Wales: prospective longitudinal cohort study.

PubMed

Hansell, Anna; Ghosh, Rebecca E; Blangiardo, Marta; Perkins, Chloe; Vienneau, Danielle; Goffe, Kayoung; Briggs, David; Gulliver, John

2016-04-01

Long-term air pollution exposure contributes to mortality but there are few studies examining effects of very long-term (>25 years) exposures. This study investigated modelled air pollution concentrations at residence for 1971, 1981, 1991 (black smoke (BS) and SO2) and 2001 (PM10) in relation to mortality up to 2009 in 367,658 members of the longitudinal survey, a 1% sample of the English Census. Outcomes were all-cause (excluding accidents), cardiovascular (CV) and respiratory mortality. BS and SO2 exposures remained associated with mortality decades after exposure-BS exposure in 1971 was significantly associated with all-cause (OR 1.02 (95% CI 1.01 to 1.04)) and respiratory (OR 1.05 (95% CI 1.01 to 1.09)) mortality in 2002-2009 (ORs expressed per 10 μg/m(3)). Largest effect sizes were seen for more recent exposures and for respiratory disease. PM10 exposure in 2001 was associated with all outcomes in 2002-2009 with stronger associations for respiratory (OR 1.22 (95% CI 1.04 to 1.44)) than CV mortality (OR 1.12 (95% CI 1.01 to 1.25)). Adjusting PM10 for past BS and SO2 exposures in 1971, 1981 and 1991 reduced the all-cause OR to 1.16 (95% CI 1.07 to 1.26) while CV and respiratory associations lost significance, suggesting confounding by past air pollution exposure, but there was no evidence for effect modification. Limitations include limited information on confounding by smoking and exposure misclassification of historic exposures. This large national study suggests that air pollution exposure has long-term effects on mortality that persist decades after exposure, and that historic air pollution exposures influence current estimates of associations between air pollution and mortality. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Historic air pollution exposure and long-term mortality risks in England and Wales: prospective longitudinal cohort study

PubMed Central

Hansell, Anna; Ghosh, Rebecca E; Blangiardo, Marta; Perkins, Chloe; Vienneau, Danielle; Goffe, Kayoung; Briggs, David; Gulliver, John

2016-01-01

Introduction Long-term air pollution exposure contributes to mortality but there are few studies examining effects of very long-term (>25 years) exposures. Methods This study investigated modelled air pollution concentrations at residence for 1971, 1981, 1991 (black smoke (BS) and SO2) and 2001 (PM10) in relation to mortality up to 2009 in 367 658 members of the longitudinal survey, a 1% sample of the English Census. Outcomes were all-cause (excluding accidents), cardiovascular (CV) and respiratory mortality. Results BS and SO2 exposures remained associated with mortality decades after exposure—BS exposure in 1971 was significantly associated with all-cause (OR 1.02 (95% CI 1.01 to 1.04)) and respiratory (OR 1.05 (95% CI 1.01 to 1.09)) mortality in 2002–2009 (ORs expressed per 10 μg/m3). Largest effect sizes were seen for more recent exposures and for respiratory disease. PM10 exposure in 2001 was associated with all outcomes in 2002–2009 with stronger associations for respiratory (OR 1.22 (95% CI 1.04 to 1.44)) than CV mortality (OR 1.12 (95% CI 1.01 to 1.25)). Adjusting PM10 for past BS and SO2 exposures in 1971, 1981 and 1991 reduced the all-cause OR to 1.16 (95% CI 1.07 to 1.26) while CV and respiratory associations lost significance, suggesting confounding by past air pollution exposure, but there was no evidence for effect modification. Limitations include limited information on confounding by smoking and exposure misclassification of historic exposures. Conclusions This large national study suggests that air pollution exposure has long-term effects on mortality that persist decades after exposure, and that historic air pollution exposures influence current estimates of associations between air pollution and mortality. PMID:26856365

Doubly robust matching estimators for high dimensional confounding adjustment.

PubMed

Antonelli, Joseph; Cefalu, Matthew; Palmer, Nathan; Agniel, Denis

2018-05-11

Valid estimation of treatment effects from observational data requires proper control of confounding. If the number of covariates is large relative to the number of observations, then controlling for all available covariates is infeasible. In cases where a sparsity condition holds, variable selection or penalization can reduce the dimension of the covariate space in a manner that allows for valid estimation of treatment effects. In this article, we propose matching on both the estimated propensity score and the estimated prognostic scores when the number of covariates is large relative to the number of observations. We derive asymptotic results for the matching estimator and show that it is doubly robust in the sense that only one of the two score models need be correct to obtain a consistent estimator. We show via simulation its effectiveness in controlling for confounding and highlight its potential to address nonlinear confounding. Finally, we apply the proposed procedure to analyze the effect of gender on prescription opioid use using insurance claims data. © 2018, The International Biometric Society.

Partial information decomposition as a spatiotemporal filter.

PubMed

Flecker, Benjamin; Alford, Wesley; Beggs, John M; Williams, Paul L; Beer, Randall D

2011-09-01

Understanding the mechanisms of distributed computation in cellular automata requires techniques for characterizing the emergent structures that underlie information processing in such systems. Recently, techniques from information theory have been brought to bear on this problem. Building on this work, we utilize the new technique of partial information decomposition to show that previous information-theoretic measures can confound distinct sources of information. We then propose a new set of filters and demonstrate that they more cleanly separate out the background domains, particles, and collisions that are typically associated with information storage, transfer, and modification in cellular automata.

The short-term effect of heat waves on mortality and its modifiers in China: an analysis from 66 communities.

PubMed

Ma, Wenjun; Zeng, Weilin; Zhou, Maigeng; Wang, Lijun; Rutherford, Shannon; Lin, Hualiang; Liu, Tao; Zhang, Yonghui; Xiao, Jianpeng; Zhang, Yewu; Wang, Xiaofeng; Gu, Xin; Chu, Cordia

2015-02-01

Many studies have reported increased mortality risk associated with heat waves. However, few have assessed the health impacts at a nation scale in a developing country. This study examines the mortality effects of heat waves in China and explores whether the effects are modified by individual-level and community-level characteristics. Daily mortality and meteorological variables from 66 Chinese communities were collected for the period 2006-2011. Heat waves were defined as ≥2 consecutive days with mean temperature ≥95th percentile of the year-round community-specific distribution. The community-specific mortality effects of heat waves were first estimated using a Distributed Lag Non-linear Model (DLNM), adjusting for potential confounders. To investigate effect modification by individual characteristics (age, gender, cause of death, education level or place of death), separate DLNM models were further fitted. Potential effect modification by community characteristics was examined using a meta-regression analysis. A total of 5.0% (95% confidence intervals (CI): 2.9%-7.2%) excess deaths were associated with heat waves in 66 Chinese communities, with the highest excess deaths in north China (6.0%, 95% CI: 1%-11.3%), followed by east China (5.2%, 95% CI: 0.4%-10.2%) and south China (4.5%, 95% CI: 1.4%-7.6%). Our results indicate that individual characteristics significantly modified heat waves effects in China, with greater effects on cardiovascular mortality, cerebrovascular mortality, respiratory mortality, the elderly, females, the population dying outside of a hospital and those with a higher education attainment. Heat wave mortality effects were also more pronounced for those living in urban cities or densely populated communities. Heat waves significantly increased mortality risk in China with apparent spatial heterogeneity, which was modified by some individual-level and community-level factors. Our findings suggest adaptation plans that target vulnerable populations in susceptible communities during heat wave events should be developed to reduce health risks. Copyright © 2014 Elsevier Ltd. All rights reserved.

Adaptive design of visual perception experiments

NASA Astrophysics Data System (ADS)

O'Connor, John D.; Hixson, Jonathan; Thomas, James M., Jr.; Peterson, Matthew S.; Parasuraman, Raja

2010-04-01

Meticulous experimental design may not always prevent confounds from affecting experimental data acquired during visual perception experiments. Although experimental controls reduce the potential effects of foreseen sources of interference, interaction, or noise, they are not always adequate for preventing the confounding effects of unforeseen forces. Visual perception experimentation is vulnerable to unforeseen confounds because of the nature of the associated cognitive processes involved in the decision task. Some confounds are beyond the control of experimentation, such as what a participant does immediately prior to experimental participation, or the participant's attitude or emotional state. Other confounds may occur through ignorance of practical control methods on the part of the experiment's designer. The authors conducted experiments related to experimental fatigue and initially achieved significant results that were, upon re-examination, attributable to a lack of adequate controls. Re-examination of the original results and the processes and events that led to them yielded a second experimental design with more experimental controls and significantly different results. The authors propose that designers of visual perception experiments can benefit from planning to use a test-fix-test or adaptive experimental design cycle, so that unforeseen confounds in the initial design can be remedied.

Instrumental Variable Methods for Continuous Outcomes That Accommodate Nonignorable Missing Baseline Values.

PubMed

Ertefaie, Ashkan; Flory, James H; Hennessy, Sean; Small, Dylan S

2017-06-15

Instrumental variable (IV) methods provide unbiased treatment effect estimation in the presence of unmeasured confounders under certain assumptions. To provide valid estimates of treatment effect, treatment effect confounders that are associated with the IV (IV-confounders) must be included in the analysis, and not including observations with missing values may lead to bias. Missing covariate data are particularly problematic when the probability that a value is missing is related to the value itself, which is known as nonignorable missingness. In such cases, imputation-based methods are biased. Using health-care provider preference as an IV method, we propose a 2-step procedure with which to estimate a valid treatment effect in the presence of baseline variables with nonignorable missing values. First, the provider preference IV value is estimated by performing a complete-case analysis using a random-effects model that includes IV-confounders. Second, the treatment effect is estimated using a 2-stage least squares IV approach that excludes IV-confounders with missing values. Simulation results are presented, and the method is applied to an analysis comparing the effects of sulfonylureas versus metformin on body mass index, where the variables baseline body mass index and glycosylated hemoglobin have missing values. Our result supports the association of sulfonylureas with weight gain. © The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Effects of early cat or dog ownership on sensitisation and asthma in a high-risk cohort without disease-related modification of exposure.

PubMed

Almqvist, Catarina; Garden, Frances; Kemp, Andrew S; Li, Qiang; Crisafulli, Daniel; Tovey, Euan R; Xuan, Wei; Marks, Guy B

2010-03-01

Variation in the observed association between pet ownership and allergic disease may be attributable to selection bias and confounding. The aim of this study was to suggest a method to assess disease-related modification of exposure and second to examine how cat acquisition or dog ownership in early life affects atopy and asthma at 5 years. Information on sociodemographic factors and cat and dog ownership was collected longitudinally in an initially cat-free Australian birth cohort based on children with a family history of asthma. At age 5 years, 516 children were assessed for wheezing, and 488 for sensitisation. Data showed that by age 5 years, 82 children had acquired a cat. Early manifestations of allergic disease did not foreshadow a reduced rate of subsequent acquisition of a cat. Independent risk factors for acquiring a cat were exposure to tobacco smoke at home odds ratio (OR) 1.92 [95% confidence interval (CI) 1.13, 3.26], maternal education < or =12 years OR 1.95 [1.08, 3.51] and dog ownership OR 2.23 [1.23, 4.05]. Cat or dog exposure in the first 5 years was associated with a decreased risk of any allergen sensitisation, OR 0.50 [0.28, 0.88] but no association with wheeze OR 0.96 [0.57, 1.61]. This risk was not affected by age at which the cat was acquired or whether the pet was kept in- or outdoors. In conclusion, cat or dog ownership reduced the risk of subsequent atopy in this high-risk birth cohort. This cannot be explained by disease-related modification of exposure. Public health recommendations on the effect of cat and dog ownership should be based on birth cohort studies where possible selection bias has been taken into account.

Heat waves in the United States: mortality risk during heat waves and effect modification by heat wave characteristics in 43 U.S. communities.

PubMed

Anderson, G Brooke; Bell, Michelle L

2011-02-01

Devastating health effects from recent heat waves, and projected increases in frequency, duration, and severity of heat waves from climate change, highlight the importance of understanding health consequences of heat waves. We analyzed mortality risk for heat waves in 43 U.S. cities (1987-2005) and investigated how effects relate to heat waves' intensity, duration, or timing in season. Heat waves were defined as ≥ 2 days with temperature ≥ 95th percentile for the community for 1 May through 30 September. Heat waves were characterized by their intensity, duration, and timing in season. Within each community, we estimated mortality risk during each heat wave compared with non-heat wave days, controlling for potential confounders. We combined individual heat wave effect estimates using Bayesian hierarchical modeling to generate overall effects at the community, regional, and national levels. We estimated how heat wave mortality effects were modified by heat wave characteristics (intensity, duration, timing in season). Nationally, mortality increased 3.74% [95% posterior interval (PI), 2.29-5.22%] during heat waves compared with non-heat wave days. Heat wave mortality risk increased 2.49% for every 1°F increase in heat wave intensity and 0.38% for every 1-day increase in heat wave duration. Mortality increased 5.04% (95% PI, 3.06-7.06%) during the first heat wave of the summer versus 2.65% (95% PI, 1.14-4.18%) during later heat waves, compared with non-heat wave days. Heat wave mortality impacts and effect modification by heat wave characteristics were more pronounced in the Northeast and Midwest compared with the South. We found higher mortality risk from heat waves that were more intense or longer, or those occurring earlier in summer. These findings have implications for decision makers and researchers estimating health effects from climate change.

Piecing together cis-regulatory networks: insights from epigenomics studies in plants.

PubMed

Huang, Shao-Shan C; Ecker, Joseph R

2018-05-01

5-Methylcytosine, a chemical modification of DNA, is a covalent modification found in the genomes of both plants and animals. Epigenetic inheritance of phenotypes mediated by DNA methylation is well established in plants. Most of the known mechanisms of establishing, maintaining and modifying DNA methylation have been worked out in the reference plant Arabidopsis thaliana. Major functions of DNA methylation in plants include regulation of gene expression and silencing of transposable elements (TEs) and repetitive sequences, both of which have parallels in mammalian biology, involve interaction with the transcriptional machinery, and may have profound effects on the regulatory networks in the cell. Methylome and transcriptome dynamics have been investigated in development and environmental responses in Arabidopsis and agriculturally and ecologically important plants, revealing the interdependent relationship among genomic context, methylation patterns, and expression of TE and protein coding genes. Analyses of methylome variation among plant natural populations and species have begun to quantify the extent of genetic control of methylome variation vs. true epimutation, and model the evolutionary forces driving methylome evolution in both short and long time scales. The ability of DNA methylation to positively or negatively modulate binding affinity of transcription factors (TFs) provides a natural link from genome sequence and methylation changes to transcription. Technologies that allow systematic determination of methylation sensitivities of TFs, in native genomic and methylation context without confounding factors such as histone modifications, will provide baseline datasets for building cell-type- and individual-specific regulatory networks that underlie the establishment and inheritance of complex traits. This article is categorized under: Laboratory Methods and Technologies > Genetic/Genomic Methods Biological Mechanisms > Regulatory Biology. © 2017 Wiley Periodicals, Inc.

Lifestyle changes lower FABP4 plasma concentration in patients with cardiovascular risk.

PubMed

Lázaro, Iolanda; Ferré, Raimon; Plana, Núria; Aragonès, Gemma; Girona, Josefa; Merino, Jordi; Heras, Mercedes; Cabré, Anna; Masana, Lluís

2012-02-01

To analyze the impact of lifestyle changes on adipocyte fatty acid-binding protein (FABP4) plasma levels in patients with cardiovascular risk. A 1-year prospective study enrolled 140 patients with cardiovascular risk but without previous cardiovascular disease to evaluate the impact of therapeutic lifestyle changes on cardiovascular risk, focusing on tobacco, nutrition education, and physical activity. The FABP4 variation was inversely associated to physical activity changes (MET·h/wk). FABP4 significantly decreased in patients with increased physical activity, whereas it increased with physical activity reduction. These FABP4 changes were also associated with modifications in body mass index and insulin resistance parameters; however, the correlations between physical activity and FABP4 remained after adjusting for these confounding variables. Changes in physical activity were the main predictors of FABP4 modifications. FABP4 reductions were directly associated with low-density lipoprotein-cholesterol and apolipoprotein B reductions. Neither tobacco cessation nor diet composition modified FABP4 concentrations. Increasing aerobic physical activity can decrease FABP4 plasma levels, independently of weight reduction. If a causal role of FABP4 in metabolic and vascular alterations could be established, our results would add new positive effects on metabolic and cardiovascular risk of both physical activity and avoiding obesity. Copyright © 2011 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.

An education gradient in health, a health gradient in education, or a confounded gradient in both?

PubMed

Lynch, Jamie L; von Hippel, Paul T

2016-04-01

There is a positive gradient associating educational attainment with health, yet the explanation for this gradient is not clear. Does higher education improve health (causation)? Do the healthy become highly educated (selection)? Or do good health and high educational attainment both result from advantages established early in the life course (confounding)? This study evaluates these competing explanations by tracking changes in educational attainment and Self-rated Health (SRH) from age 15 to age 31 in the National Longitudinal Study of Youth, 1997 cohort. Ordinal logistic regression confirms that high-SRH adolescents are more likely to become highly educated. This is partly because adolescent SRH is associated with early advantages including adolescents' academic performance, college plans, and family background (confounding); however, net of these confounders adolescent SRH still predicts adult educational attainment (selection). Fixed-effects longitudinal regression shows that educational attainment has little causal effect on SRH at age 31. Completion of a high school diploma or associate's degree has no effect on SRH, while completion of a bachelor's or graduate degree have effects that, though significant, are quite small (less than 0.1 points on a 5-point scale). While it is possible that educational attainment would have greater effect on health at older ages, at age 31 what we see is a health gradient in education, shaped primarily by selection and confounding rather than by a causal effect of education on health. Copyright © 2016 Elsevier Ltd. All rights reserved.

The ACCE method: an approach for obtaining quantitative or qualitative estimates of residual confounding that includes unmeasured confounding

PubMed Central

Smith, Eric G.

2015-01-01

Background:  Nonrandomized studies typically cannot account for confounding from unmeasured factors.  Method:  A method is presented that exploits the recently-identified phenomenon of  “confounding amplification” to produce, in principle, a quantitative estimate of total residual confounding resulting from both measured and unmeasured factors.  Two nested propensity score models are constructed that differ only in the deliberate introduction of an additional variable(s) that substantially predicts treatment exposure.  Residual confounding is then estimated by dividing the change in treatment effect estimate between models by the degree of confounding amplification estimated to occur, adjusting for any association between the additional variable(s) and outcome. Results:  Several hypothetical examples are provided to illustrate how the method produces a quantitative estimate of residual confounding if the method’s requirements and assumptions are met.  Previously published data is used to illustrate that, whether or not the method routinely provides precise quantitative estimates of residual confounding, the method appears to produce a valuable qualitative estimate of the likely direction and general size of residual confounding. Limitations:  Uncertainties exist, including identifying the best approaches for: 1) predicting the amount of confounding amplification, 2) minimizing changes between the nested models unrelated to confounding amplification, 3) adjusting for the association of the introduced variable(s) with outcome, and 4) deriving confidence intervals for the method’s estimates (although bootstrapping is one plausible approach). Conclusions:  To this author’s knowledge, it has not been previously suggested that the phenomenon of confounding amplification, if such amplification is as predictable as suggested by a recent simulation, provides a logical basis for estimating total residual confounding. The method's basic approach is straightforward.  The method's routine usefulness, however, has not yet been established, nor has the method been fully validated. Rapid further investigation of this novel method is clearly indicated, given the potential value of its quantitative or qualitative output. PMID:25580226

Does Educational Status Impact Adult Mortality in Denmark? A Twin Approach

PubMed Central

Madsen, Mia; Andersen, Anne-Marie Nybo; Christensen, Kaare; Andersen, Per Kragh; Osler, Merete

2010-01-01

To disentangle an independent effect of educational status on mortality risk from direct and indirect selection mechanisms, the authors used a discordant twin pair design, which allowed them to isolate the effect of education by means of adjustment for genetic and environmental confounding per design. The study is based on data from the Danish Twin Registry and Statistics Denmark. Using Cox regression, they estimated hazard ratios for mortality according to the highest attained education among 5,260 monozygotic and 11,088 dizygotic same-sex twin pairs born during 1921–1950 and followed during 1980–2008. Both standard cohort and intrapair analyses were conducted separately for zygosity, gender, and birth cohort. Educational differences in mortality were demonstrated in the standard cohort analyses but attenuated in the intrapair analyses in all subgroups but men born during 1921–1935, and no effect modification by zygosity was observed. Hence, the results are most compatible with an effect of early family environment in explaining the educational inequality in mortality. However, large educational differences were still reflected in mortality risk differences within twin pairs, thus supporting some degree of independent effect of education. In addition, the effect of education may be more pronounced in older cohorts of Danish men. PMID:20530466

Teacher Quality at the High-School Level: The Importance of Accounting for Tracks. Working Paper 17722. Revised

ERIC Educational Resources Information Center

Jackson, C. Kirabo

2013-01-01

Unlike in elementary school, high-school teacher effects may be confounded with both selection to tracks and unobserved track-level treatments. I document sizable confounding track effects, and show that traditional tests for the existence of teacher effects are likely biased. After accounting for these biases, high-school algebra and English…

Survival on Home Dialysis in New Zealand

PubMed Central

Marshall, Mark R.; Walker, Rachael C.; Polkinghorne, Kevan R.; Lynn, Kelvin L.

2014-01-01

Background New Zealand (NZ) has a high prevalence of both peritoneal dialysis (PD) and home haemodialysis (HD) relative to other countries, and probably less selection bias. We aimed to determine if home dialysis associates with better survival than facility HD by simultaneous comparisons of the three modalities. Methods We analysed survival by time-varying dialysis modality in New Zealanders over a 15-year period to 31-Dec-2011, adjusting for patient co-morbidity by Cox proportional hazards multivariate regression. Results We modelled 6,419 patients with 3,254 deaths over 20,042 patient-years of follow-up. Patients treated with PD and facility HD are similar; those on home HD are younger and healthier. Compared to facility HD, home dialysis (as a unified category) associates with an overall 13% lower mortality risk. Home HD associates with a 52% lower mortality risk. PD associates with a 20% lower mortality risk in the early period (<3 years) that is offset by a 33% greater mortality risk in the late period (>3 years), with no overall net effect. There was effect modification and less observable benefit associated with PD in those with diabetes mellitus, co-morbidity, and in NZ Maori and Pacific People. There was no effect modification by age or by era. Conclusion Our study supports the culture of home dialysis in NZ, and suggests that the extent and duration of survival benefit associated with early PD may be greater than appreciated. We are planning further analyses to exclude residual confounding from unmeasured co-morbidity and other sociodemographic factors using database linkage to NZ government datasets. Finally, our results suggest further research into the practice of PD in NZ Maori and Pacific People, as well as definitive study to determine the best timing for switching from PD in the late phase. PMID:24806458

Occupational exposures to solvents and metals are associated with fixed airflow obstruction.

PubMed

Alif, Sheikh M; Dharmage, Shyamali C; Benke, Geza; Dennekamp, Martine; Burgess, John A; Perret, Jennifer L; Lodge, Caroline J; Morrison, Stephen; Johns, David P; Giles, Graham G; Gurrin, Lyle C; Thomas, Paul S; Hopper, John L; Wood-Baker, Richard; Thompson, Bruce R; Feather, Iain H; Vermeulen, Roel; Kromhout, Hans; Walters, E Haydn; Abramson, Michael J; Matheson, Melanie C

2017-11-01

Objectives This study investigated the associations between occupational exposures to solvents and metals and fixed airflow obstruction (AO) using post-bronchodilator spirometry. Methods We included 1335 participants from the 2002-2008 follow-up of the Tasmanian Longitudinal Health Study. Ever-exposure and cumulative exposure-unit (EU) years were calculated using the ALOHA plus job exposure matrix (JEM). Fixed AO was defined as post-bronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) <0.7 and FEV 1 /FVC

Confounding adjustment in comparative effectiveness research conducted within distributed research networks.

PubMed

Toh, Sengwee; Gagne, Joshua J; Rassen, Jeremy A; Fireman, Bruce H; Kulldorff, Martin; Brown, Jeffrey S

2013-08-01

A distributed research network (DRN) of electronic health care databases, in which data reside behind the firewall of each data partner, can support a wide range of comparative effectiveness research (CER) activities. An essential component of a fully functional DRN is the capability to perform robust statistical analyses to produce valid, actionable evidence without compromising patient privacy, data security, or proprietary interests. We describe the strengths and limitations of different confounding adjustment approaches that can be considered in observational CER studies conducted within DRNs, and the theoretical and practical issues to consider when selecting among them in various study settings. Several methods can be used to adjust for multiple confounders simultaneously, either as individual covariates or as confounder summary scores (eg, propensity scores and disease risk scores), including: (1) centralized analysis of patient-level data, (2) case-centered logistic regression of risk set data, (3) stratified or matched analysis of aggregated data, (4) distributed regression analysis, and (5) meta-analysis of site-specific effect estimates. These methods require different granularities of information be shared across sites and afford investigators different levels of analytic flexibility. DRNs are growing in use and sharing of highly detailed patient-level information is not always feasible in DRNs. Methods that incorporate confounder summary scores allow investigators to adjust for a large number of confounding factors without the need to transfer potentially identifiable information in DRNs. They have the potential to let investigators perform many analyses traditionally conducted through a centralized dataset with detailed patient-level information.

Measurement of exercise-induced oxidative stress in lymphocytes.

PubMed

Turner, James E; Bosch, Jos A; Aldred, Sarah

2011-10-01

Vigorous exercise is associated with oxidative stress, a state that involves modifications to bodily molecules due to release of pro-oxidant species. Assessment of such modifications provides non-specific measures of oxidative stress in human tissues and blood, including circulating lymphocytes. Lymphocytes are a very heterogeneous group of white blood cells, consisting of subtypes that have different functions in immunity. Importantly, exercise drastically changes the lymphocyte composition in blood by increasing the numbers of some subsets, while leaving other cells unaffected. This fact may imply that observed changes in oxidative stress markers are confounded by changes in lymphocyte composition. For example, lymphocyte subsets may differ in exposure to oxidative stress because of subset differences in cell division and the acquisition of cytotoxic effector functions. The aim of the present review is to raise awareness of interpretational issues related to the assessment of oxidative stress in lymphocytes with exercise and to address the relevance of lymphocyte subset phenotyping in these contexts.

Early Exposure to Traffic-Related Air Pollution, Respiratory Symptoms at 4 Years of Age, and Potential Effect Modification by Parental Allergy, Stressful Family Events, and Sex: A Prospective Follow-up Study of the PARIS Birth Cohort

PubMed Central

Rancière, Fanny; Bougas, Nicolas; Viola, Malika; Momas, Isabelle

2016-01-01

Background: The relation between traffic-related air pollution (TRAP) exposure and the incidence of asthma/allergy in preschool children has been widely studied, but results remain heterogeneous, possibly due to differences in methodology and susceptibility to TRAP. Objectives: We aimed to study the relation of early TRAP exposure with the development of respiratory/allergic symptoms and asthma during preschool years, and to investigate parental allergy, “stressful” family events, and sex as possible effect modifiers. Methods: We examined data of 2,015 children from the PARIS birth cohort followed up with repeated questionnaires completed by parents until age 4 years. TRAP exposure in each child’s first year of life was estimated by nitrogen oxides (NOx) air dispersion modeling, taking into account both home and day care locations. Association between TRAP exposure and patterns of wheezing, dry night cough, and rhinitis symptoms was studied using multinomial logistic regression models adjusted for potential confounders. Effect modification by parental history of allergy, stressful family events, and sex was investigated. Results: An interquartile range (26 μg/m3) increase in NOx levels was associated with an increased odds ratio (OR) of persistent wheezing at 4 years (adjusted OR = 1.27; 95% confidence interval: 1.09, 1.47). TRAP exposure was positively associated with persistent wheeze, dry cough, and rhinitis symptoms among children with a parental allergy, those experiencing stressful family events, and boys, but not in children whose parents did not have allergies or experience stressful events, or in girls (all interaction p-values < 0.2). Conclusions: This study supports the hypothesis that not all preschool children are equal regarding TRAP health effects. Parental history of allergy, stressful family events, and male sex may increase their susceptibility to adverse respiratory effects of early TRAP exposure. Citation: Rancière F, Bougas N, Viola M, Momas I. 2017. Early exposure to traffic-related air pollution, respiratory symptoms at 4 years of age, and potential effect modification by parental allergy, stressful family events, and sex: a prospective follow-up study of the PARIS birth cohort. Environ Health Perspect 125:737–745; http://dx.doi.org/10.1289/EHP239 PMID:27219743

Elevations in mortality due to weaning persist into the second year of life among uninfected children born to HIV-infected mothers

PubMed Central

Kuhn, Louise; Sinkala, Moses; Semrau, Katherine; Kankasa, Chipepo; Kasonde, Prisca; Mwiya, Mwiya; Hu, Chih-Chi; Tsai, Wei-Yann; Thea, Donald M.; Aldrovandi, Grace M.

2009-01-01

Background Early weaning has been recommended to reduce postnatal HIV transmission. We evaluated the safety of stopping breastfeeding at different ages for mortality of uninfected children born to HIV-infected mothers. Methods During a trial of early weaning, 958 HIV-infected mothers and their infants were recruited and followed from birth to 24 months in Lusaka, Zambia. Half of the cohort was randomized to wean abruptly at 4 months and the other half to continue breastfeeding. We examined associations between uninfected child mortality and actual breastfeeding duration investigating possible confounding and effect modification. Results The mortality rate among 749 uninfected children was 9.4% by 12 months and 13.6% by 24 months. Weaning during the interval encouraged by the protocol (4-5 months) was associated with a 2.03-fold increased risk of mortality (95% CI: 1.13 - 3.65), weaning 6-11 months a 3.54-fold increase (95% CI: 1.68 - 7.46) and 12-18 months a 4.22-fold increase (95% CI: 1.59 - 11.24). Significant effect modification was detected such that risks associated with weaning were stronger among infants born to mothers with higher CD4 counts (>350 cells/mL). Conclusion Shortening the normal duration of breastfeeding for uninfected children born to HIV-infected mothers living in low resource settings is associated with significant increases mortality extending into the second year of life. Intensive nutritional and counseling interventions reduce, but do not eliminate, this excess mortality. PMID:20047479

Restricted spatial regression in practice: Geostatistical models, confounding, and robustness under model misspecification

USGS Publications Warehouse

Hanks, Ephraim M.; Schliep, Erin M.; Hooten, Mevin B.; Hoeting, Jennifer A.

2015-01-01

In spatial generalized linear mixed models (SGLMMs), covariates that are spatially smooth are often collinear with spatially smooth random effects. This phenomenon is known as spatial confounding and has been studied primarily in the case where the spatial support of the process being studied is discrete (e.g., areal spatial data). In this case, the most common approach suggested is restricted spatial regression (RSR) in which the spatial random effects are constrained to be orthogonal to the fixed effects. We consider spatial confounding and RSR in the geostatistical (continuous spatial support) setting. We show that RSR provides computational benefits relative to the confounded SGLMM, but that Bayesian credible intervals under RSR can be inappropriately narrow under model misspecification. We propose a posterior predictive approach to alleviating this potential problem and discuss the appropriateness of RSR in a variety of situations. We illustrate RSR and SGLMM approaches through simulation studies and an analysis of malaria frequencies in The Gambia, Africa.

Development of a banding database for North Pacific albatross: Implications for future data collection

USGS Publications Warehouse

Doherty, P.F.; Kendall, W.L.; Sillett, S.; Gustafson, M.; Flint, B.; Naughton, M.; Robbins, C.S.; Pyle, P.; Macintyre, Ian G.

2006-01-01

The effects of fishery practices on black-footed (Phoebastria nigripes) and Laysan albatross (Phoebastria immutabilis) continue to be a source of contention and uncertainty. Some of this uncertainty is a result of a lack of estimates of albatross demographic parameters such as survival. To begin to address these informational needs, a database of albatross banding and encounter records was constructed. Due to uncertainty concerning data collection and validity of assumptions required for mark-recapture analyses, these data should be used with caution. Although demographic parameter estimates are of interest to many, band loss rates, temporary emigration rates, and discontinuous banding effort can confound these estimates. We suggest a number of improvements in data collection that can help ameliorate problems, including the use of double banding and collecting data using a `robust? design. Additionally, sustained banding and encounter efforts are needed to maximize the value of these data. With these modifications, the usefulness of the banding data could be improved markedly.

Using propensity scores to estimate the effects of insecticides on stream invertebrates from observational data

USGS Publications Warehouse

Lester L. Yuan,; Amina I. Pollard,; Carlisle, Daren M.

2009-01-01

Analyses of observational data can provide insights into relationships between environmental conditions and biological responses across a broader range of natural conditions than experimental studies, potentially complementing insights gained from experiments. However, observational data must be analyzed carefully to minimize the likelihood that confounding variables bias observed relationships. Propensity scores provide a robust approach for controlling for the effects of measured confounding variables when analyzing observational data. Here, we use propensity scores to estimate changes in mean invertebrate taxon richness in streams that have experienced insecticide concentrations that exceed aquatic life use benchmark concentrations. A simple comparison of richness in sites exposed to elevated insecticides with those that were not exposed suggests that exposed sites had on average 6.8 fewer taxa compared to unexposed sites. The presence of potential confounding variables makes it difficult to assert a causal relationship from this simple comparison. After controlling for confounding factors using propensity scores, the difference in richness between exposed and unexposed sites was reduced to 4.1 taxa, a difference that was still statistically significant. Because the propensity score analysis controlled for the effects of a wide variety of possible confounding variables, we infer that the change in richness observed in the propensity score analysis was likely caused by insecticide exposure.

Using propensity scores to estimate the effects of insecticides on stream invertebrates from observational data

USGS Publications Warehouse

Yuan, L.L.; Pollard, A.I.; Carlisle, D.M.

2009-01-01

Analyses of observational data can provide insights into relationships between environmental conditions and biological responses across a broader range of natural conditions than experimental studies, potentially complementing insights gained from experiments. However, observational data must be analyzed carefully to minimize the likelihood that confounding variables bias observed relationships. Propensity scores provide a robust approach for controlling for the effects of measured confounding variables when analyzing observational data. Here, we use propensity scores to estimate changes in mean invertebrate taxon richness in streams that have experienced insecticide concentrations that exceed aquatic life use benchmark concentrations. A simple comparison of richness in sites exposed to elevated insecticides with those that were not exposed suggests that exposed sites had on average 6.8 fewer taxa compared to unexposed sites. The presence of potential confounding variables makes it difficult to assert a causal relationship from this simple comparison. After controlling for confounding factors using propensity scores, the difference in richness between exposed and unexposed sites was reduced to 4.1 taxa, a difference that was still statistically significant. Because the propensity score analysis controlled for the effects of a wide variety of possible confounding variables, we infer that the change in richness observed in the propensity score analysis was likely caused by insecticide exposure. ?? 2009 SETAC.

Toxicity of the molybdate anion in soil is partially explained by effects of the accompanying cation or by soil pH.

PubMed

Buekers, Jurgen; Mertens, Jelle; Smolders, Erik

2010-06-01

Previous studies have shown that toxicity of cationic trace metals in soil is partially confounded by effects of the accompanying anions. A similar assessment is reported here for toxicity of an oxyanion, i.e., molybdate (MoO(4) (2-)), the soil toxicity of which is relatively unexplored. Solubility and toxicity were compared between the soluble sodium molybdate (Na(2)MoO(4)) and the sparingly soluble molybdenum trioxide (MoO(3)). Confounding effects of salinity were excluded by referencing the Na(2)MoO(4) effect to that of sodium chloride (NaCl). The pH decrease from the acid MoO(3) amendment was equally referenced to a hydrochloric (HCl) treatment or a lime-controlled MoO(3) treatment. The concentrations of molybdenum (Mo) in soil solution or calcium chloride (CaCl(2)) 0.01 M extracts were only marginally affected by either MoO(3) or Na(2)MoO(4) as an Mo source after 10 to 13 days of equilibration. Effects of Mo on soil nitrification were fully confounded by associated changes in salinity or pH. Effects of Mo on growth of wheat seedlings (Triticum aestivum L) were more pronounced than those on nitrification, and toxicity thresholds were unaffected by the form of added Mo. The Mo thresholds for wheat growth were not confounded by pH or salinity at incipient toxicity. It is concluded that oxyanion toxicity might be confounded in relatively insensitive tests for which reference treatments should be included. Copyright 2010 SETAC.

Vulnerability to extreme-heat-associated hospitalization in three counties in Michigan, USA, 2000-2009

NASA Astrophysics Data System (ADS)

Ogbomo, Adesuwa S.; Gronlund, Carina J.; O'Neill, Marie S.; Konen, Tess; Cameron, Lorraine; Wahl, Robert

2017-05-01

With climate change, extreme heat (EH) events are increasing, so it is important to understand who is vulnerable to heat-associated morbidity. We determined the association between EH and hospitalizations for all natural causes; cardiovascular, respiratory, and renal diseases; diabetes mellitus; and acute myocardial infarction in Michigan, USA, at different intensities and durations. We assessed confounding by ozone and how individual characteristics and health insurance payer (a proxy for income) modified these associations. We obtained Michigan Inpatient Database, National Climatic Data Center, and US Environmental Protection Agency ozone data for May-September, 2000-2009 for three Michigan counties. We employed a case-crossover design and modeled EH as an indicator for temperature above the 95th, 97th, or 99th percentile thresholds for 1, 2, 3, or 4 days. We examined effect modification by patient age, race, sex, and health insurance payer and pooled the county results. Among non-whites, the pooled odds ratio for hospitalization on EH (97th percentile threshold) vs. non-EH days for renal diseases was 1.37 (95 % CI = 1.13-1.66), which increased with increasing EH intensity, but was null among whites (OR = 1.00, 95 % CI = 0.81, 1.25). We observed a null association between EH and cardiovascular hospitalization. EH (99th percentile threshold) was associated with myocardial infarction hospitalizations. Confounding by ozone was minimal. EH was associated with hospitalizations for renal disease among non-whites. This information on vulnerability to heat-associated morbidity helps characterize the public health burden of EH and target interventions including patient education.

Epidemiologic studies of electric and magnetic fields and cancer: strategies for extending knowledge.

PubMed Central

Savitz, D A

1993-01-01

Epidemiologic research concerning electric and magnetic fields in relation to cancer has focused on the potential etiologic roles of residential exposure on childhood cancer and occupational exposure on adult leukemia and brain cancer. Future residential studies must concentrate on exposure assessment that is enhanced by developing models of historical exposure, assessment of the relation between magnetic fields and wire codes, and consideration of alternate exposure indices. Study design issues deserving attention include possible biases in random digit dialing control selection, consideration of the temporal course of exposure and disease, and acquisition of the necessary information to assess the potential value of ecologic studies. Highest priorities are comprehensive evaluation of exposure patterns and sources and examination of the sociology and geography of residential wire codes. Future occupational studies should also concentrate on improved exposure assessment with increased attention to nonutility worker populations and development of historical exposure indicators that are superior to job titles alone. Potential carcinogens in the workplace that could act as confounders need to be more carefully examined. The temporal relation between exposure and disease and possible effect modification by other workplace agents should be incorporated into future studies. The most pressing need is for measurement of exposure patterns in a variety of worker populations and performance of traditional epidemiologic evaluations of cancer occurrence. The principal source of bias toward the null is nondifferential misclassification of exposure with improvements expected to enhance any true etiologic association that is present. Biases away from the null might include biased control selection in residential studies and chemical carcinogens acting as confounders in occupational studies. PMID:8206046

Good research practices for comparative effectiveness research: approaches to mitigate bias and confounding in the design of nonrandomized studies of treatment effects using secondary data sources: the International Society for Pharmacoeconomics and Outcomes Research Good Research Practices for Retrospective Database Analysis Task Force Report--Part II.

PubMed

Cox, Emily; Martin, Bradley C; Van Staa, Tjeerd; Garbe, Edeltraut; Siebert, Uwe; Johnson, Michael L

2009-01-01

The goal of comparative effectiveness analysis is to examine the relationship between two variables, treatment, or exposure and effectiveness or outcome. Unlike data obtained through randomized controlled trials, researchers face greater challenges with causal inference with observational studies. Recognizing these challenges, a task force was formed to develop a guidance document on methodological approaches to addresses these biases. The task force was commissioned and a Chair was selected by the International Society for Pharmacoeconomics and Outcomes Research Board of Directors in October 2007. This report, the second of three reported in this issue of the Journal, discusses the inherent biases when using secondary data sources for comparative effectiveness analysis and provides methodological recommendations to help mitigate these biases. The task force report provides recommendations and tools for researchers to mitigate threats to validity from bias and confounding in measurement of exposure and outcome. Recommendations on design of study included: the need for data analysis plan with causal diagrams; detailed attention to classification bias in definition of exposure and clinical outcome; careful and appropriate use of restriction; extreme care to identify and control for confounding factors, including time-dependent confounding. Design of nonrandomized studies of comparative effectiveness face several daunting issues, including measurement of exposure and outcome challenged by misclassification and confounding. Use of causal diagrams and restriction are two techniques that can improve the theoretical basis for analyzing treatment effects in study populations of more homogeneity, with reduced loss of generalizability.

Leveraging Hierarchical Population Structure in Discrete Association Studies

PubMed Central

Carlson, Jonathan; Kadie, Carl; Mallal, Simon; Heckerman, David

2007-01-01

Population structure can confound the identification of correlations in biological data. Such confounding has been recognized in multiple biological disciplines, resulting in a disparate collection of proposed solutions. We examine several methods that correct for confounding on discrete data with hierarchical population structure and identify two distinct confounding processes, which we call coevolution and conditional influence. We describe these processes in terms of generative models and show that these generative models can be used to correct for the confounding effects. Finally, we apply the models to three applications: identification of escape mutations in HIV-1 in response to specific HLA-mediated immune pressure, prediction of coevolving residues in an HIV-1 peptide, and a search for genotypes that are associated with bacterial resistance traits in Arabidopsis thaliana. We show that coevolution is a better description of confounding in some applications and conditional influence is better in others. That is, we show that no single method is best for addressing all forms of confounding. Analysis tools based on these models are available on the internet as both web based applications and downloadable source code at http://atom.research.microsoft.com/bio/phylod.aspx. PMID:17611623

Early Exposure to Traffic-Related Air Pollution, Respiratory Symptoms at 4 Years of Age, and Potential Effect Modification by Parental Allergy, Stressful Family Events, and Sex: A Prospective Follow-up Study of the PARIS Birth Cohort.

PubMed

Rancière, Fanny; Bougas, Nicolas; Viola, Malika; Momas, Isabelle

2017-04-01

The relation between traffic-related air pollution (TRAP) exposure and the incidence of asthma/allergy in preschool children has been widely studied, but results remain heterogeneous, possibly due to differences in methodology and susceptibility to TRAP. We aimed to study the relation of early TRAP exposure with the development of respiratory/allergic symptoms and asthma during preschool years, and to investigate parental allergy, "stressful" family events, and sex as possible effect modifiers. We examined data of 2,015 children from the PARIS birth cohort followed up with repeated questionnaires completed by parents until age 4 years. TRAP exposure in each child's first year of life was estimated by nitrogen oxides (NO x ) air dispersion modeling, taking into account both home and day care locations. Association between TRAP exposure and patterns of wheezing, dry night cough, and rhinitis symptoms was studied using multinomial logistic regression models adjusted for potential confounders. Effect modification by parental history of allergy, stressful family events, and sex was investigated. An interquartile range (26 μg/m 3 ) increase in NO x levels was associated with an increased odds ratio (OR) of persistent wheezing at 4 years (adjusted OR = 1.27; 95% confidence interval: 1.09, 1.47). TRAP exposure was positively associated with persistent wheeze, dry cough, and rhinitis symptoms among children with a parental allergy, those experiencing stressful family events, and boys, but not in children whose parents did not have allergies or experience stressful events, or in girls (all interaction p -values < 0.2). This study supports the hypothesis that not all preschool children are equal regarding TRAP health effects. Parental history of allergy, stressful family events, and male sex may increase their susceptibility to adverse respiratory effects of early TRAP exposure.

The impact of ambient fine particles on influenza transmission and the modification effects of temperature in China: A multi-city study.

PubMed

Chen, Gongbo; Zhang, Wenyi; Li, Shanshan; Zhang, Yongming; Williams, Gail; Huxley, Rachel; Ren, Hongyan; Cao, Wei; Guo, Yuming

2017-01-01

There is good evidence that air pollution is a risk factor for adverse respiratory and vascular health outcomes. However, data are limited as to whether ambient fine particles contribute to the transmission of influenza and if so, how the association is modified by weather conditions. We examined the relationship between ambient PM 2.5 and influenza incidence at the national level in China and explored the associations at different temperatures. Daily data on concentrations of particulate matter with aerodynamic diameter<2.5μm (PM 2.5 ) and influenza incidence counts were collected in 47 Chinese cities. A Poisson regression model was used to estimate the city-specific PM 2.5 -influenza association, after controlling for potential confounders. Then, a random-effect meta-analysis was used to pool the effects at national level. In addition, stratified analyses were performed to examine modification effects of ambient temperature. For single lag models, the highest effect of ambient PM 2.5 on influenza incidence appeared at lag day 2, with relative risk (RR) of 1.015 (95% confidence interval (CI): 1.004, 1.025) associated with a 10μg/m 3 increase in PM 2.5 . For moving average lag models, the significant association was found at lag 2-3days, with RR of 1.020 (95% CI: 1.006, 1.034). The RR of influenza transmission associated with PM 2.5 was higher for cold compared with hot days. Overall, 10.7% of incident influenza cases may result from exposure to ambient PM 2.5 . Ambient PM 2.5 may increase the risk of exposure to influenza in China especially on cooler days. Control measures to reduce PM 2.5 concentrations could potentially also be of benefit in lowering the risk of exposure and subsequent transmission of influenza in China. Copyright © 2016 Elsevier Ltd. All rights reserved.

Correction of confounding bias in non-randomized studies by appropriate weighting.

PubMed

Schmoor, Claudia; Gall, Christine; Stampf, Susanne; Graf, Erika

2011-03-01

In non-randomized studies, the assessment of a causal effect of treatment or exposure on outcome is hampered by possible confounding. Applying multiple regression models including the effects of treatment and covariates on outcome is the well-known classical approach to adjust for confounding. In recent years other approaches have been promoted. One of them is based on the propensity score and considers the effect of possible confounders on treatment as a relevant criterion for adjustment. Another proposal is based on using an instrumental variable. Here inference relies on a factor, the instrument, which affects treatment but is thought to be otherwise unrelated to outcome, so that it mimics randomization. Each of these approaches can basically be interpreted as a simple reweighting scheme, designed to address confounding. The procedures will be compared with respect to their fundamental properties, namely, which bias they aim to eliminate, which effect they aim to estimate, and which parameter is modelled. We will expand our overview of methods for analysis of non-randomized studies to methods for analysis of randomized controlled trials and show that analyses of both study types may target different effects and different parameters. The considerations will be illustrated using a breast cancer study with a so-called Comprehensive Cohort Study design, including a randomized controlled trial and a non-randomized study in the same patient population as sub-cohorts. This design offers ideal opportunities to discuss and illustrate the properties of the different approaches. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

"A Bayesian sensitivity analysis to evaluate the impact of unmeasured confounding with external data: a real world comparative effectiveness study in osteoporosis".

PubMed

Zhang, Xiang; Faries, Douglas E; Boytsov, Natalie; Stamey, James D; Seaman, John W

2016-09-01

Observational studies are frequently used to assess the effectiveness of medical interventions in routine clinical practice. However, the use of observational data for comparative effectiveness is challenged by selection bias and the potential of unmeasured confounding. This is especially problematic for analyses using a health care administrative database, in which key clinical measures are often not available. This paper provides an approach to conducting a sensitivity analyses to investigate the impact of unmeasured confounding in observational studies. In a real world osteoporosis comparative effectiveness study, the bone mineral density (BMD) score, an important predictor of fracture risk and a factor in the selection of osteoporosis treatments, is unavailable in the data base and lack of baseline BMD could potentially lead to significant selection bias. We implemented Bayesian twin-regression models, which simultaneously model both the observed outcome and the unobserved unmeasured confounder, using information from external sources. A sensitivity analysis was also conducted to assess the robustness of our conclusions to changes in such external data. The use of Bayesian modeling in this study suggests that the lack of baseline BMD did have a strong impact on the analysis, reversing the direction of the estimated effect (odds ratio of fracture incidence at 24 months: 0.40 vs. 1.36, with/without adjusting for unmeasured baseline BMD). The Bayesian twin-regression models provide a flexible sensitivity analysis tool to quantitatively assess the impact of unmeasured confounding in observational studies. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Effect of Vitamin D Receptor Activation on the AGE/RAGE System and Myeloperoxidase in Chronic Kidney Disease Patients

PubMed Central

Pizzini, Patrizia; Cutrupi, Sebastiano; Tripepi, Rocco; Vilasi, Antonio; Tripepi, Giovanni; Mallamaci, Francesca

2017-01-01

Vitamin D receptor (VDR) activation has been reported to increase circulating levels of the advanced glycation end products (AGE) and their decoy receptor (RAGE). However, until now, the effect of VDR activation on AGE and RAGE has not been tested in the setting of a randomized, double-blind clinical trial. We have therefore analyzed the effect of VDR activation by paricalcitol on pentosidine, S100A12/ENRAGE, and RAGE and on established biomarkers of oxidative stress like myeloperoxidase in CKD patients in the PENNY trial. At baseline, human S100A12/ENRAGE, RAGE, and myeloperoxidase, but not pentosidine, were intercorrelated, and the association between S100A12/ENRAGE and myeloperoxidase (r = 0.71, P < 0.001) was the strongest among these correlations. Paricalcitol failed to modify biomarkers of the AGE/RAGE system and myeloperoxidase in unadjusted and adjusted analyses by the generalized linear model (GLM). No effect modification by other risk factors was registered. Paricalcitol does not modify biomarkers of the AGE/RAGE system and myeloperoxidase in CKD patients. The apparent increase in RAGE levels by VDR activation reported in previous uncontrolled studies is most likely due to confounding factors rather than to VDR activation per se. This trial is registered with NCT01680198. PMID:29362665

Adjusting for geographic variation in observational comparative effectiveness studies: a case study of antipsychotics using state Medicaid data.

PubMed

Root, Elisabeth Dowling; Thomas, Deborah S K; Campagna, Elizabeth J; Morrato, Elaine H

2014-08-27

Area-level variation in treatment and outcomes may be a potential source of confounding bias in observational comparative effectiveness studies. This paper demonstrates how to use exploratory spatial data analysis (ESDA) and spatial statistical methods to investigate and control for these potential biases. The case presented compares the effectiveness of two antipsychotic treatment strategies: oral second-generation antipsychotics (SGAs) vs. long-acting paliperiodone palmitate (PP). A new-start cohort study was conducted analyzing patient-level administrative claims data (8/1/2008-4/30/2011) from Missouri Medicaid. ESDA techniques were used to examine spatial patterns of antipsychotic prescriptions and outcomes (hospitalization and emergency department (ED) visits). Likelihood of mental health-related outcomes were compared between patients starting PP (N = 295) and oral SGAs (N = 8,626) using multilevel logistic regression models adjusting for patient composition (demographic and clinical factors) and geographic region. ESDA indicated significant spatial variation in antipsychotic prescription patterns and moderate variation in hospitalization and ED visits thereby indicating possible confounding by geography. In the multilevel models for this antipsychotic case example, patient composition represented a stronger source of confounding than geographic context. Because geographic variation in health care delivery is ubiquitous, it could be a comparative effectiveness research (CER) best practice to test for possible geographic confounding in observational data. Though the magnitude of the area-level geography effects were small in this case, they were still statistically significant and should therefore be examined as part of this observational CER study. More research is needed to better estimate the range of confounding due to geography across different types of observational comparative effectiveness studies and healthcare utilization outcomes.

The impact of confounder selection in propensity scores when applied to prospective cohort studies in pregnancy.

PubMed

Xu, Ronghui; Hou, Jue; Chambers, Christina D

2018-06-01

Our work was motivated by small cohort studies on the risk of birth defects in infants born to pregnant women exposed to medications. We controlled for confounding using propensity scores (PS). The extremely rare events setting renders the matching or stratification infeasible. In addition, the PS itself may be formed via different approaches to select confounders from a relatively long list of potential confounders. We carried out simulation experiments to compare different combinations of approaches: IPW or regression adjustment, with 1) including all potential confounders without selection, 2) selection based on univariate association between the candidate variable and the outcome, 3) selection based on change in effects (CIE). The simulation showed that IPW without selection leads to extremely large variances in the estimated odds ratio, which help to explain the empirical data analysis results that we had observed. Copyright © 2018 Elsevier Inc. All rights reserved.

Effects of categorization method, regression type, and variable distribution on the inflation of Type-I error rate when categorizing a confounding variable.

PubMed

Barnwell-Ménard, Jean-Louis; Li, Qing; Cohen, Alan A

2015-03-15

The loss of signal associated with categorizing a continuous variable is well known, and previous studies have demonstrated that this can lead to an inflation of Type-I error when the categorized variable is a confounder in a regression analysis estimating the effect of an exposure on an outcome. However, it is not known how the Type-I error may vary under different circumstances, including logistic versus linear regression, different distributions of the confounder, and different categorization methods. Here, we analytically quantified the effect of categorization and then performed a series of 9600 Monte Carlo simulations to estimate the Type-I error inflation associated with categorization of a confounder under different regression scenarios. We show that Type-I error is unacceptably high (>10% in most scenarios and often 100%). The only exception was when the variable categorized was a continuous mixture proxy for a genuinely dichotomous latent variable, where both the continuous proxy and the categorized variable are error-ridden proxies for the dichotomous latent variable. As expected, error inflation was also higher with larger sample size, fewer categories, and stronger associations between the confounder and the exposure or outcome. We provide online tools that can help researchers estimate the potential error inflation and understand how serious a problem this is. Copyright © 2014 John Wiley & Sons, Ltd.

Analyzing partially missing confounder information in comparative effectiveness and safety research of therapeutics.

PubMed

Toh, Sengwee; García Rodríguez, Luis A; Hernán, Miguel A

2012-05-01

Electronic healthcare databases are commonly used in comparative effectiveness and safety research of therapeutics. Many databases now include additional confounder information in a subset of the study population through data linkage or data collection. We described and compared existing methods for analyzing such datasets. Using data from The Health Improvement Network and the relation between non-steroidal anti-inflammatory drugs and upper gastrointestinal bleeding as an example, we employed several methods to handle partially missing confounder information. The crude odds ratio (OR) of upper gastrointestinal bleeding was 1.50 (95% confidence interval: 0.98, 2.28) among selective cyclo-oxygenase-2 inhibitor initiators (n = 43 569) compared with traditional non-steroidal anti-inflammatory drug initiators (n = 411 616). The OR dropped to 0.81 (0.52, 1.27) upon adjustment for confounders recorded for all patients. When further considering three additional variables missing in 22% of the study population (smoking, alcohol consumption, body mass index), the OR was between 0.80 and 0.83 for the missing-category approach, the missing-indicator approach, single imputation by the most common category, multiple imputation by chained equations, and propensity score calibration. The OR was 0.65 (0.39, 1.09) and 0.67 (0.38, 1.16) for the unweighted and the inverse probability weighted complete-case analysis, respectively. Existing methods for handling partially missing confounder data require different assumptions and may produce different results. The unweighted complete-case analysis, the missing-category/indicator approach, and single imputation require often unrealistic assumptions and should be avoided. In this study, differences across methods were not substantial, likely due to relatively low proportion of missingness and weak confounding effect by the three additional variables upon adjustment for other variables. Copyright © 2012 John Wiley & Sons, Ltd.

Antidepressant response in patients with major depression exposed to NSAIDs: a pharmacovigilance study.

PubMed

Gallagher, Patience J; Castro, Victor; Fava, Maurizio; Weilburg, Jeffrey B; Murphy, Shawn N; Gainer, Vivian S; Churchill, Susanne E; Kohane, Isaac S; Iosifescu, Dan V; Smoller, Jordan W; Perlis, Roy H

2012-10-01

OBJECTIVE It has been suggested that there is a mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with antidepressant response, and poorer outcomes among NSAID-treated patients were reported in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. To attempt to confirm this association in an independent population-based treatment cohort and explore potential confounding variables, the authors examined use of NSAIDs and related medications among 1,528 outpatients in a New England health care system. METHOD Treatment outcomes were classified using a validated machine learning tool applied to electronic medical records. Logistic regression was used to examine the association between medication exposure and treatment outcomes, adjusted for potential confounding variables. To further elucidate confounding and treatment specificity of the observed effects, data from the STAR*D study were reanalyzed. RESULTS NSAID exposure was associated with a greater likelihood of depression classified as treatment resistant compared with depression classified as responsive to selective serotonin reuptake inhibitors (odds ratio=1.55, 95% CI=1.21-2.00). This association was apparent in the NSAIDs-only group but not in those using other agents with NSAID-like mechanisms (cyclooxygenase-2 inhibitors and salicylates). Inclusion of age, sex, ethnicity, and measures of comorbidity and health care utilization in regression models indicated confounding; association with outcome was no longer significant in fully adjusted models. Reanalysis of STAR*D results likewise identified an association in NSAIDs but not NSAID-like drugs, with more modest effects persisting after adjustment for potential confounding variables. CONCLUSIONS These results support an association between NSAID use and poorer antidepressant outcomes in major depressive disorder but indicate that some of the observed effect may be a result of confounding.

A method for sensitivity analysis to assess the effects of measurement error in multiple exposure variables using external validation data.

PubMed

Agogo, George O; van der Voet, Hilko; van 't Veer, Pieter; Ferrari, Pietro; Muller, David C; Sánchez-Cantalejo, Emilio; Bamia, Christina; Braaten, Tonje; Knüppel, Sven; Johansson, Ingegerd; van Eeuwijk, Fred A; Boshuizen, Hendriek C

2016-10-13

Measurement error in self-reported dietary intakes is known to bias the association between dietary intake and a health outcome of interest such as risk of a disease. The association can be distorted further by mismeasured confounders, leading to invalid results and conclusions. It is, however, difficult to adjust for the bias in the association when there is no internal validation data. We proposed a method to adjust for the bias in the diet-disease association (hereafter, association), due to measurement error in dietary intake and a mismeasured confounder, when there is no internal validation data. The method combines prior information on the validity of the self-report instrument with the observed data to adjust for the bias in the association. We compared the proposed method with the method that ignores the confounder effect, and with the method that ignores measurement errors completely. We assessed the sensitivity of the estimates to various magnitudes of measurement error, error correlations and uncertainty in the literature-reported validation data. We applied the methods to fruits and vegetables (FV) intakes, cigarette smoking (confounder) and all-cause mortality data from the European Prospective Investigation into Cancer and Nutrition study. Using the proposed method resulted in about four times increase in the strength of association between FV intake and mortality. For weakly correlated errors, measurement error in the confounder minimally affected the hazard ratio estimate for FV intake. The effect was more pronounced for strong error correlations. The proposed method permits sensitivity analysis on measurement error structures and accounts for uncertainties in the reported validity coefficients. The method is useful in assessing the direction and quantifying the magnitude of bias in the association due to measurement errors in the confounders.

Does consideration of larger study areas yield more accurate estimates of air pollution health effects? An illustration of the bias-variance trade-off in air pollution epidemiology.

PubMed

Pedersen, Marie; Siroux, Valérie; Pin, Isabelle; Charles, Marie Aline; Forhan, Anne; Hulin, Agnés; Galineau, Julien; Lepeule, Johanna; Giorgis-Allemand, Lise; Sunyer, Jordi; Annesi-Maesano, Isabella; Slama, Rémy

2013-10-01

Spatially-resolved air pollution models can be developed in large areas. The resulting increased exposure contrasts and population size offer opportunities to better characterize the effect of atmospheric pollutants on respiratory health. However the heterogeneity of these areas may also enhance the potential for confounding. We aimed to discuss some analytical approaches to handle this trade-off. We modeled NO2 and PM10 concentrations at the home addresses of 1082 pregnant mothers from EDEN cohort living in and around urban areas, using ADMS dispersion model. Simulations were performed to identify the best strategy to limit confounding by unmeasured factors varying with area type. We examined the relation between modeled concentrations and respiratory health in infants using regression models with and without adjustment or interaction terms with area type. Simulations indicated that adjustment for area limited the bias due to unmeasured confounders varying with area at the costs of a slight decrease in statistical power. In our cohort, rural and urban areas differed for air pollution levels and for many factors associated with respiratory health and exposure. Area tended to modify effect measures of air pollution on respiratory health. Increasing the size of the study area also increases the potential for residual confounding. Our simulations suggest that adjusting for type of area is a good option to limit residual confounding due to area-associated factors without restricting the area size. Other statistical approaches developed in the field of spatial epidemiology are an alternative to control for poorly-measured spatially-varying confounders. © 2013 Elsevier Ltd. All rights reserved.

Are Interactions between cis-Regulatory Variants Evidence for Biological Epistasis or Statistical Artifacts?

PubMed

Fish, Alexandra E; Capra, John A; Bush, William S

2016-10-06

The importance of epistasis-or statistical interactions between genetic variants-to the development of complex disease in humans has been controversial. Genome-wide association studies of statistical interactions influencing human traits have recently become computationally feasible and have identified many putative interactions. However, statistical models used to detect interactions can be confounded, which makes it difficult to be certain that observed statistical interactions are evidence for true molecular epistasis. In this study, we investigate whether there is evidence for epistatic interactions between genetic variants within the cis-regulatory region that influence gene expression after accounting for technical, statistical, and biological confounding factors. We identified 1,119 (FDR = 5%) interactions that appear to regulate gene expression in human lymphoblastoid cell lines, a tightly controlled, largely genetically determined phenotype. Many of these interactions replicated in an independent dataset (90 of 803 tested, Bonferroni threshold). We then performed an exhaustive analysis of both known and novel confounders, including ceiling/floor effects, missing genotype combinations, haplotype effects, single variants tagged through linkage disequilibrium, and population stratification. Every interaction could be explained by at least one of these confounders, and replication in independent datasets did not protect against some confounders. Assuming that the confounding factors provide a more parsimonious explanation for each interaction, we find it unlikely that cis-regulatory interactions contribute strongly to human gene expression, which calls into question the relevance of cis-regulatory interactions for other human phenotypes. We additionally propose several best practices for epistasis testing to protect future studies from confounding. Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Propensity score models in observational comparative effectiveness studies: cornerstone of design or statistical afterthought?

PubMed

Robinson, John W

2012-03-01

Propensity score models are increasingly used in observational comparative effectiveness studies to reduce confounding by covariates that are associated with both a study outcome and treatment choice. Any such potentially confounding covariate will bias estimation of the effect of treatment on the outcome, unless the distribution of that covariate is well-balanced between treatment and control groups. Constructing a subsample of treated and control subjects who are matched on estimated propensity scores is a means of achieving such balance for covariates that are included in the propensity score model. If, during study design, investigators assemble a comprehensive inventory of known and suspected potentially confounding covariates, examination of how well this inventory is covered by the chosen dataset yields an assessment of the extent of bias reduction that is possible by matching on estimated propensity scores. These considerations are explored by examining the designs of three recently published comparative effectiveness studies.

Mismeasurement and the resonance of strong confounders: uncorrelated errors.

PubMed

Marshall, J R; Hastrup, J L

1996-05-15

Greenland first documented (Am J Epidemiol 1980; 112:564-9) that error in the measurement of a confounder could resonate--that it could bias estimates of other study variables, and that the bias could persist even with statistical adjustment for the confounder as measured. An important question is raised by this finding: can such bias be more than trivial within the bounds of realistic data configurations? The authors examine several situations involving dichotomous and continuous data in which a confounder and a null variable are measured with error, and they assess the extent of resultant bias in estimates of the effect of the null variable. They show that, with continuous variables, measurement error amounting to 40% of observed variance in the confounder could cause the observed impact of the null study variable to appear to alter risk by as much as 30%. Similarly, they show, with dichotomous independent variables, that 15% measurement error in the form of misclassification could lead the null study variable to appear to alter risk by as much as 50%. Such bias would result only from strong confounding. Measurement error would obscure the evidence that strong confounding is a likely problem. These results support the need for every epidemiologic inquiry to include evaluations of measurement error in each variable considered.

Controlling for seasonal patterns and time varying confounders in time-series epidemiological models: a simulation study.

PubMed

Perrakis, Konstantinos; Gryparis, Alexandros; Schwartz, Joel; Le Tertre, Alain; Katsouyanni, Klea; Forastiere, Francesco; Stafoggia, Massimo; Samoli, Evangelia

2014-12-10

An important topic when estimating the effect of air pollutants on human health is choosing the best method to control for seasonal patterns and time varying confounders, such as temperature and humidity. Semi-parametric Poisson time-series models include smooth functions of calendar time and weather effects to control for potential confounders. Case-crossover (CC) approaches are considered efficient alternatives that control seasonal confounding by design and allow inclusion of smooth functions of weather confounders through their equivalent Poisson representations. We evaluate both methodological designs with respect to seasonal control and compare spline-based approaches, using natural splines and penalized splines, and two time-stratified CC approaches. For the spline-based methods, we consider fixed degrees of freedom, minimization of the partial autocorrelation function, and general cross-validation as smoothing criteria. Issues of model misspecification with respect to weather confounding are investigated under simulation scenarios, which allow quantifying omitted, misspecified, and irrelevant-variable bias. The simulations are based on fully parametric mechanisms designed to replicate two datasets with different mortality and atmospheric patterns. Overall, minimum partial autocorrelation function approaches provide more stable results for high mortality counts and strong seasonal trends, whereas natural splines with fixed degrees of freedom perform better for low mortality counts and weak seasonal trends followed by the time-season-stratified CC model, which performs equally well in terms of bias but yields higher standard errors. Copyright © 2014 John Wiley & Sons, Ltd.

Associations of Blood and Urinary Mercury with Hypertension in U.S. Adults: the NHANES 2003–2006

PubMed Central

Park, Sung Kyun; Lee, Sunghee; Basu, Niladri; Franzblau, Alfred

2013-01-01

Background Few studies have examined the association between hypertension and mercury exposure in the general population. We examined cross-sectional associations between blood (mainly methylmercury) or urinary mercury (mainly inorganic mercury) and hypertension in representative U.S. adults and effect modifications by dietary omega-3 fatty acids and serum selenium. Methods We examined 6,607 adults aged 20 years or older, using the National Health and Nutrition Examination Survey (NHANES) from 2003/2004 to 2005/2006 (2,201 adults were available for urinary mercury from NHANES 2003–2006; 2,117 available for serum selenium from NHANES 2003–2004 aged 40 years or older). The average of omega-3 fatty acids from two 24-hour recalls was calculated. Results The weighted prevalence of hypertension was 32.2%. The geometric means (95% confidence intervals) of blood total and urinary mercury were 1.03 (0.95, 1.11) µg/L and 0.51 (0.47, 0.54) µg/L, respectively. The adjusted odds ratios for a doubling increase in blood mercury and urinary mercury were 0.94 (0.87 to 1.01) and 0.87 (0.78 to 0.99), respectively, after adjusting for potential confounders. The associations remained similar, even after adjusting for either omega-3 fatty acids or selenium or both. No significant effect modification by either omega-3 fatty acids or selenium was observed. Conclusions In this cross-sectional study of the U.S. general population, we found no association of hypertension with blood mercury but a suggestive inverse association with urinary mercury. Future prospective studies are warranted to confirm these findings. PMID:23472608

Food insecurity, social networks and symptoms of depression among men and women in rural Uganda: a cross-sectional, population-based study.

PubMed

Perkins, Jessica M; Nyakato, Viola N; Kakuhikire, Bernard; Tsai, Alexander C; Subramanian, S V; Bangsberg, David R; Christakis, Nicholas A

2018-04-01

To assess the association between food insecurity and depression symptom severity stratified by sex, and test for evidence of effect modification by social network characteristics. A population-based cross-sectional study. The nine-item Household Food Insecurity Access Scale captured food insecurity. Five name generator questions elicited network ties. A sixteen-item version of the Hopkins Symptom Checklist for Depression captured depression symptom severity. Linear regression was used to estimate the association between food insecurity and depression symptom severity while adjusting for potential confounders and to test for potential network moderators. In-home survey interviews in south-western Uganda. All adult residents across eight rural villages; 96 % response rate (n 1669). Severe food insecurity was associated with greater depression symptom severity (b=0·4, 95 % CI 0·3, 0·5, P<0·001 for women; b=0·3, 95 % CI 0·2, 0·4, P<0·001 for men). There was no evidence of effect modification by social network factors for women. However, for men who are highly embedded within in their village social network, and (separately) for men who have few poor contacts in their personal network, the relationship between severe food insecurity and depression symptoms was stronger than for men on the periphery of their village social network, and for men with many poor personal network contacts, respectively. In this population-based study from rural Uganda, food insecurity was associated with mental health for both men and women. Future research is needed on networks and food insecurity-related shame in relation to depression symptoms among food-insecure men.

Associations between disability prevalence and local-area characteristics in a general community-living population.

PubMed

Philibert, M D; Pampalon, R; Hamel, D; Daniel, M

2013-10-01

Disability is understood to arise from person-environment interactions. Hence, heterogeneity in local-area characteristics should be associated with local-area variation in disability prevalence. This study evaluated the associations of disability prevalence with local-area socioeconomic status and contextual features. Disability prevalence was obtained from the Canada census of 2001 for the entire province of Québec at the level of dissemination areas (617 individuals on average) based on responses from 20% of the population. Data on local-area characteristics were urban-rural denomination, social and material deprivation, active and collective commuting, residential stability, and housing quality. Associations between local-area characteristics and disability prevalence were assessed using multilevel logistic regressions. Disability was associated with local-area socioeconomic status and contextual characteristics, and heterogeneity in these factors accounted for urban-rural differences in disability prevalence. Associations between contextual features and disability prevalence were confounded by local-area socioeconomic status. Some associations between local-area socioeconomic status and disability prevalence were moderated by contextual characteristics. The importance of this effect modification is greater when expressed in terms of the absolute magnitude of disability than in the relative likelihood of disability. Explanation of rural-urban differences by the contribution of other local-area characteristics is consistent with the conceptualization of urban-rural categories as the reflection of spatially varying ensembles of compositional and contextual factors. Although local-area socioeconomic status explains most variability in disability prevalence, this study shows that contextual characteristics are relevant to analyses of the spatial patterning of disability as they predict spatial variations of disability, sometimes in interaction with socioeconomic status. This study demonstrates that absolute and relative perspectives on effect modification may lead to differing conclusions. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Time-varying effect moderation using the structural nested mean model: estimation using inverse-weighted regression with residuals

PubMed Central

Almirall, Daniel; Griffin, Beth Ann; McCaffrey, Daniel F.; Ramchand, Rajeev; Yuen, Robert A.; Murphy, Susan A.

2014-01-01

This article considers the problem of examining time-varying causal effect moderation using observational, longitudinal data in which treatment, candidate moderators, and possible confounders are time varying. The structural nested mean model (SNMM) is used to specify the moderated time-varying causal effects of interest in a conditional mean model for a continuous response given time-varying treatments and moderators. We present an easy-to-use estimator of the SNMM that combines an existing regression-with-residuals (RR) approach with an inverse-probability-of-treatment weighting (IPTW) strategy. The RR approach has been shown to identify the moderated time-varying causal effects if the time-varying moderators are also the sole time-varying confounders. The proposed IPTW+RR approach provides estimators of the moderated time-varying causal effects in the SNMM in the presence of an additional, auxiliary set of known and measured time-varying confounders. We use a small simulation experiment to compare IPTW+RR versus the traditional regression approach and to compare small and large sample properties of asymptotic versus bootstrap estimators of the standard errors for the IPTW+RR approach. This article clarifies the distinction between time-varying moderators and time-varying confounders. We illustrate the methodology in a case study to assess if time-varying substance use moderates treatment effects on future substance use. PMID:23873437

A Comprehensive Analysis of the SRS-Schwab Adult Spinal Deformity Classification and Confounding Variables: A Prospective, Non-US Cross-sectional Study in 292 Patients.

PubMed

Hallager, Dennis Winge; Hansen, Lars Valentin; Dragsted, Casper Rokkjær; Peytz, Nina; Gehrchen, Martin; Dahl, Benny

2016-05-01

Cross-sectional analyses on a consecutive, prospective cohort. To evaluate the ability of the Scoliosis Research Society (SRS)-Schwab Adult Spinal Deformity Classification to group patients by widely used health-related quality-of-life (HRQOL) scores and examine possible confounding variables. The SRS-Schwab Adult Spinal Deformity Classification includes sagittal modifiers considered important for HRQOL and the clinical impact of the classification has been validated in patients from the International Spine Study Group database; however, equivocal results were reported for the Pelvic Tilt modifier and potential confounding variables were not evaluated. Between March 2013 and May 2014, all adult spinal deformity patients from our outpatient clinic with sufficient radiographs were prospectively enrolled. Analyses of HRQOL variance and post hoc analyses were performed for each SRS-Schwab modifier. Age, history of spine surgery, and aetiology of spinal deformity were considered potential confounders and their influence on the association between SRS-Schwab modifiers and aggregated Oswestry Disability Index (ODI) scores was evaluated with multivariate proportional odds regressions. P values were adjusted for multiple testing. Two hundred ninety-two of 460 eligible patients were included for analyses. The SRS-Schwab Classification significantly discriminated HRQOL scores between normal and abnormal sagittal modifier classifications. Individual grade comparisons showed equivocal results; however, Pelvic Tilt grade + versus +  + did not discriminate patients according to any HRQOL score. All modifiers showed significant proportional odds for worse aggregated ODI scores with increasing grade levels and the effects were robust to confounding. However, age group and aetiology had individual significant effects. The SRS-Schwab sagittal modifiers reliably grouped patients graded 0 versus + / +  + according to the most widely used HRQOL scores and the effects of increasing grade level on odds for worse ODI scores remained significant after adjusting for potential confounders. However, effects of age group and aetiology should not be neglected. 3.

Another look at the safety effects of horizontal curvature on rural two-lane highways.

PubMed

Saleem, Taha; Persaud, Bhagwant

2017-09-01

Crash Modification Factors (CMFs) are used to represent the effects on crashes of changes to highway design elements and are usually obtained from observational studies based on reported crashes. The design element of interest for this paper is horizontal curvature on rural 2-lane highways. The data for this study came from the Washington State database in the Highway Safety Information System (HSIS). Crash prediction models are developed for curve sections on rural 2-lane highway and the tangent sections up- and down-stream of the curve sections. Different negative binomial models were developed for segments on level grades (<3%), moderate grades (3-6%), and steep grades (>6%) to account for the confounding effects of gradient. The relationships between crashes at different traffic volumes and deflection angles are explored to illustrate how to get estimates of CMFs for increases in the minimum radius, considering the effect of increased tangent length for sharper curves, an effect that is overlooked in the Highway Safety Manual CMF, in addition to the effect of gradient. The results of that exploration indicated that even at different design speeds and deflection angles, the CMF estimates for incremental increases in radius lie within the same range, and that the crash reduction rate (CRR) is higher at segments on higher grades compared to the ones on lower grades. Copyright © 2017 Elsevier Ltd. All rights reserved.

Obesity paradox and mortality in adults with and without incident type 2 diabetes: a matched population-level cohort study

PubMed Central

Badrick, Ellena; Sperrin, Matthew; Buchan, Iain E

2017-01-01

Objective Among adults with type 2 diabetes (T2D), several (but not all) studies show that being overweight (body mass index (BMI): 25.0–29.9 kg/m2) or obese I (BMI: 30.0–34.9 kg/m2) near the time of diagnosis, is unexpectedly associated with reduced all-cause mortality compared with normal weight—the obesity paradox. We addressed whether this observation is causal (eg, a true protective effect); due to confounding (including effect modification); or due to selection (‘collider’) bias. Research design and methods We performed a matched population-level cohort study using primary care records from Salford, UK (1995–2012) in 10 464 patients with incident T2D paired (1:3) with 31 020 individuals who never developed T2D. We estimated HRs for associations of BMI with all-cause mortality using Cox models, stratified by smoking status. Results Median follow-up was 8.7 years. For never smokers, the hazard of all-cause mortality increased from 25 kg/m2, in a linear manner, with increasing BMI in the T2D cohort (HR per 5 kg/m2: 1.23, ptrend<0.001) and in the non-diabetes cohort (HR per 5 kg/m2: 1.34, ptrend<0.001). In contrast, among ever smokers, BMI-mortality relationships were U-shaped in the T2D and non-diabetes cohorts. Evidence of the obesity paradox in ever smokers, with and without T2D, argued against a selection bias, but supported a contribution of effect modification by smoking (pinteraction=0.009). Results were stable to various sensitivity analyses. Conclusions In this cohort, the obesity paradox is mainly explained by smoking as an effect modifier. These findings indicate that the obesity paradox does not challenge standard weight management recommendations among T2D patients. PMID:28321314

Psychosocial Assessment of Self-Harm Patients and Risk of Repeat Presentation: An Instrumental Variable Analysis Using Time of Hospital Presentation.

PubMed

Carroll, Robert; Metcalfe, Chris; Steeg, Sarah; Davies, Neil M; Cooper, Jayne; Kapur, Nav; Gunnell, David

2016-01-01

Clinical guidelines have recommended psychosocial assessment of self-harm patients for years, yet estimates of its impact on the risk of repeat self-harm vary. Assessing the association of psychosocial assessment with risk of repeat self-harm is challenging due to the effects of confounding by indication. We analysed data from a cohort study of 15,113 patients presenting to the emergency departments of three UK hospitals to investigate the association of psychosocial assessment with risk of repeat hospital presentation for self-harm. Time of day of hospital presentation was used as an instrument for psychosocial assessment, attempting to control for confounding by indication. Conventional regression analysis suggested psychosocial assessment was not associated with risk of repeat self-harm within 12 months (Risk Difference (RD) 0.00 95% confidence interval (95%CI) -0.01 to 0.02). In contrast, IV analysis suggested risk of repeat self-harm was reduced by 18% (RD -0.18, 95%CI -0.32 to -0.03) in those patients receiving a psychosocial assessment. However, the instrument of time of day did not remove all potential effects of confounding by indication, suggesting the IV effect estimate may be biased. We found that psychosocial assessments reduce risk of repeat self-harm. This is in-line with other non-randomised studies based on populations in which allocation to assessment was less subject to confounding by indication. However, as our instrument did not fully balance important confounders across time of day, the IV effect estimate should be interpreted with caution.

On the use and misuse of scalar scores of confounders in design and analysis of observational studies.

PubMed

Pfeiffer, R M; Riedl, R

2015-08-15

We assess the asymptotic bias of estimates of exposure effects conditional on covariates when summary scores of confounders, instead of the confounders themselves, are used to analyze observational data. First, we study regression models for cohort data that are adjusted for summary scores. Second, we derive the asymptotic bias for case-control studies when cases and controls are matched on a summary score, and then analyzed either using conditional logistic regression or by unconditional logistic regression adjusted for the summary score. Two scores, the propensity score (PS) and the disease risk score (DRS) are studied in detail. For cohort analysis, when regression models are adjusted for the PS, the estimated conditional treatment effect is unbiased only for linear models, or at the null for non-linear models. Adjustment of cohort data for DRS yields unbiased estimates only for linear regression; all other estimates of exposure effects are biased. Matching cases and controls on DRS and analyzing them using conditional logistic regression yields unbiased estimates of exposure effect, whereas adjusting for the DRS in unconditional logistic regression yields biased estimates, even under the null hypothesis of no association. Matching cases and controls on the PS yield unbiased estimates only under the null for both conditional and unconditional logistic regression, adjusted for the PS. We study the bias for various confounding scenarios and compare our asymptotic results with those from simulations with limited sample sizes. To create realistic correlations among multiple confounders, we also based simulations on a real dataset. Copyright © 2015 John Wiley & Sons, Ltd.

Identification of confounders in the assessment of the relationship between lead exposure and child development.

PubMed

Tong, I S; Lu, Y

2001-01-01

To explore the best approach to identify and adjust for confounders in epidemiologic practice. In the Port Pirie cohort study, the selection of covariates was based on both a priori and an empirical consideration. In an assessment of the relationship between exposure to environmental lead and child development, change-in-estimate (CE) and significance testing (ST) criteria were compared in identifying potential confounders. The Pearson correlation coefficients were used to evaluate the potential for collinearity between pairs of major quantitative covariates. In multivariate analyses, the effects of confounding factors were assessed with multiple linear regression models. The nature and number of covariates selected varied with different confounder selection criteria and different cutoffs. Four covariates (i.e., quality of home environment, socioeconomic status (SES), maternal intelligence, and parental smoking behaviour) met the conventional CE criterion (> or =10%), whereas 14 variables met the ST criterion (p < or = 0.25). However, the magnitude of the relationship between blood lead concentration and children's IQ differed slightly after adjustment for confounding, using either the CE (partial regression coefficient: -4.4; 95% confidence interval (CI): -0.5 to -8.3) or ST criterion (-4.3; 95% CI: -0.2 to -8.4). Identification and selection of confounding factors need to be viewed cautiously in epidemiologic studies. Either the CE (e.g., > or = 10%) or ST (e.g., p < or = 0.25) criterion may be implemented in identification of a potential confounder if a study sample is sufficiently large, and both the methods are subject to arbitrariness of selecting a cut-off point. In this study, the CE criterion (i.e., > or = 10%) appears to be more stringent than the ST method (i.e., p < or = 0.25) in the identification of confounders. However, the ST rule cannot be used to determine the trueness of confounding because it cannot reflect the causal relationship between the confounder and outcome. This study shows the complexities one can expect to encounter in the identification of and adjustment for confounders.

Effect of Bolus Viscosity on the Safety and Efficacy of Swallowing and the Kinematics of the Swallow Response in Patients with Oropharyngeal Dysphagia: White Paper by the European Society for Swallowing Disorders (ESSD).

PubMed

Newman, Roger; Vilardell, Natàlia; Clavé, Pere; Speyer, Renée

2016-04-01

Fluid thickening is a well-established management strategy for oropharyngeal dysphagia (OD). However, the effects of thickening agents on the physiology of impaired swallow responses are not fully understood, and there is no agreement on the degree of bolus thickening. To review the literature and to produce a white paper of the European Society for Swallowing Disorders (ESSD) describing the evidence in the literature on the effect that bolus modification has upon the physiology, efficacy and safety of swallowing in adults with OD. A systematic search was performed using the electronic Pubmed and Embase databases. Articles in English available up to July 2015 were considered. The inclusion criteria swallowing studies on adults over 18 years of age; healthy people or patients with oropharyngeal dysphagia; bolus modification; effects of bolus modification on swallow safety (penetration/aspiration) and efficacy; and/or physiology and original articles written in English. The exclusion criteria consisted of oesophageal dysphagia and conference abstracts or presentations. The quality of the selected papers and the level of research evidence were assessed by standard quality assessments. At the end of the selection process, 33 articles were considered. The quality of all included studies was assessed using systematic, reproducible, and quantitative tools (Kmet and NHMRC) concluding that all the selected articles reached a valid level of evidence. The literature search gathered data from various sources, ranging from double-blind randomised control trials to systematic reviews focused on changes occurring in swallowing physiology caused by thickened fluids. Main results suggest that increasing bolus viscosity (a) results in increased safety of swallowing, (b) also results in increased amounts of oral and/or pharyngeal residue which may result in post-swallow airway invasion, (c) impacts the physiology with increased lingual pressure patterns, no major changes in impaired airway protection mechanisms, and controversial effects on oral and pharyngeal transit time, hyoid displacements, onset of UOS opening and bolus velocity-with several articles suggesting the therapeutic effect of thickeners is also due to intrinsic bolus properties, (d) reduces palatability of thickened fluids and (e) correlates with increased risk of dehydration and decreased quality of life although the severity of dysphagia may be an confounding factor. The ESSD concludes that there is evidence for increasing viscosity to reduce the risk of airway invasion and that it is a valid management strategy for OD. However, new thickening agents should be developed to avoid the negative effects of increasing viscosity on residue, palatability, and treatment compliance. New randomised controlled trials should establish the optimal viscosity level for each phenotype of dysphagic patients and descriptors, terminology and viscosity measurements must be standardised. This white paper is the first step towards the development of a clinical guideline on bolus modification for patients with oropharyngeal dysphagia.

Past, present, and future of epigenetics applied to livestock breeding

PubMed Central

González-Recio, Oscar; Toro, Miguel A.; Bach, Alex

2015-01-01

This article reviews the concept of Lamarckian inheritance and the use of the term epigenetics in the field of animal genetics. Epigenetics was first coined by Conrad Hal Waddington (1905–1975), who derived the term from the Aristotelian word epigenesis. There exists some controversy around the word epigenetics and its broad definition. It includes any modification of the expression of genes due to factors other than mutation in the DNA sequence. This involves DNA methylation, post-translational modification of histones, but also linked to regulation of gene expression by non-coding RNAs, genome instabilities or any other force that could modify a phenotype. There is little evidence of the existence of transgenerational epigenetic inheritance in mammals, which may commonly be confounded with environmental forces acting simultaneously on an individual, her developing fetus and the germ cell lines of the latter, although it could have an important role in the cellular energetic status of cells. Finally, we review some of the scarce literature on the use of epigenetics in animal breeding programs. PMID:26442117

Use of instrumental variables in the analysis of generalized linear models in the presence of unmeasured confounding with applications to epidemiological research.

PubMed

Johnston, K M; Gustafson, P; Levy, A R; Grootendorst, P

2008-04-30

A major, often unstated, concern of researchers carrying out epidemiological studies of medical therapy is the potential impact on validity if estimates of treatment are biased due to unmeasured confounders. One technique for obtaining consistent estimates of treatment effects in the presence of unmeasured confounders is instrumental variables analysis (IVA). This technique has been well developed in the econometrics literature and is being increasingly used in epidemiological studies. However, the approach to IVA that is most commonly used in such studies is based on linear models, while many epidemiological applications make use of non-linear models, specifically generalized linear models (GLMs) such as logistic or Poisson regression. Here we present a simple method for applying IVA within the class of GLMs using the generalized method of moments approach. We explore some of the theoretical properties of the method and illustrate its use within both a simulation example and an epidemiological study where unmeasured confounding is suspected to be present. We estimate the effects of beta-blocker therapy on one-year all-cause mortality after an incident hospitalization for heart failure, in the absence of data describing disease severity, which is believed to be a confounder. 2008 John Wiley & Sons, Ltd

Epidemiological survey of oral lesions in children and adolescents in a Brazilian population.

PubMed

Pessôa, Camila Porto; Alves, Técia Daltro Borges; dos Santos, Nilton César Nogueira; dos Santos, Heloísa Laís Rosário; Azevedo, Alana de Cássia Silva; dos Santos, Jean Nunes; Oliveira, Márcio Campos

2015-11-01

To identify the most frequent oral lesions in children and adolescents in Reference Units of Oral Lesions of Public Universities of Bahia, Brazil, in the period between 1996 and 2010, and estimate the association between socio-demographic factors and type of oral lesions found. Cross-sectional study using secondary data obtained from medical records, records of requests and reports of biopsies from patients aged between 0 and 19 years treated in Reference Units of Oral Lesions of Public Universities in Bahia, Brazil, in the period between 1996 and 2010. For data analysis, we used descriptive analysis of the variables, bivariate analysis by calculating the prevalence ratios (PR) to assess the association between oral lesions and gender, age and skin color, and the analysis of potential modifying and confounding effects by logistic regression modeling. To calculate the p-value of associations, we used the chi-square test, and p<0.05 was considered statistically significant. There were 360 records of patients between 0 and 19 years (8.7% of total records). The results revealed 72 different types of lesions. The most prevalent lesions were mucoceles (14.2%), fibroma (5.6%) and pyogenic granuloma (5.3%). The variable "age" was the only socio-demographic characteristics among those analyzed that showed a statistically significant association with both neoplastic and non-neoplastic lesions, according to bivariate analysis, considering the rates adjusted for potential confounders. Neoplastic lesions appeared more often in the age group 0-9 years, while the non-neoplastic lesions were more prevalent in individuals 10-19 years. There was no effect modification noted in the predictive models analyzed. The study identified the existence of a broad range of oral lesions affecting children and adolescents. Most of the lesions found were of the non-neoplastic type. The age of individuals was associated with the type of oral lesion found. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Serum Insulin-Like Growth Factor 1 and the Risk of Ischemic Stroke: The Framingham Study.

PubMed

Saber, Hamidreza; Himali, Jayandra J; Beiser, Alexa S; Shoamanesh, Ashkan; Pikula, Aleksandra; Roubenoff, Ronenn; Romero, Jose R; Kase, Carlos S; Vasan, Ramachandran S; Seshadri, Sudha

2017-07-01

Low insulin-like growth factor 1 (IGF-1) has been associated with increased risk of atherosclerosis and atrial fibrillation in cross-sectional studies. Yet, prospective data linking IGF-1 levels to the development of ischemic stroke remain inconclusive. We examined prospectively the association between serum IGF-1 levels and incident ischemic stroke. We measured serum IGF-1 levels in 757 elderly individuals (mean age 79±5, 62% women), free of prevalent stroke, from the Framingham original cohort participants at the 22nd examination cycle (1990-1994) and were followed up for the development of ischemic stroke. Cox models were used to relate IGF-1 levels to the risk for incident ischemic stroke, adjusted for potential confounders. During a mean follow-up of 10.2 years, 99 individuals developed ischemic stroke. After adjustment for age, sex, and potential confounders, higher IGF-1 levels were associated with a lower risk of incident ischemic stroke, with subjects in the lowest quintile of IGF-1 levels having a 2.3-fold higher risk of incident ischemic stroke (95% confidence interval, 1.09-5.06; P =0.03) as compared with those in the top quintile. We observed an effect modification by diabetes mellitus and waist-hip ratio for the association between IGF-1 and ischemic stroke ( P <0.1). In subgroup analyses, the effects were restricted to subjects with diabetics and those in top waist-hip ratio quartile, in whom each standard deviation increase in IGF-1 was associated with a 61% (hazard ratio, 0.39; 95% confidence interval, 0.20-0.78; P =0.007) and 41% (hazard ratio, 0.59; 95% confidence interval, 0.37-0.95; P =0.031) lower risk of incident ischemic stroke, respectively. IGF-1 levels were inversely associated with ischemic stroke, especially among persons with insulin resistance. © 2017 American Heart Association, Inc.

Negative affectivity: moderator or confound in emotional dissonance-outcome relationships?

PubMed

Abraham, R

1999-01-01

This study was an examination of the impact of negative affectivity on relationships between emotional dissonance, job satisfaction, and emotional exhaustion. Negative affectivity is the predisposition to view life in negative terms. Emotional dissonance originates from the conflict between expressed and experienced emotions. In organizations that require the expression of positive emotions, high negative affectivity individuals may experience conflict between expressed, positive emotions and felt, negative emotions. A moderator effect exists when high negative affectivity individuals experience greater job dissatisfaction and emotional exhaustion. Alternatively, negative affectivity may exert a confounding effect through its relationship to both emotional dissonance and its outcomes. Empirical tests showed that negative affectivity moderated the emotional dissonance-job satisfaction relationship and confounded the emotional dissonance-emotional exhaustion relationship.

Do time-invariant confounders explain away the association between job stress and workers' mental health? Evidence from Japanese occupational panel data.

PubMed

Oshio, Takashi; Tsutsumi, Akizumi; Inoue, Akiomi

2015-02-01

It is well known that job stress is negatively related to workers' mental health, but most recent studies have not controlled for unobserved time-invariant confounders. In the current study, we attempted to validate previous observations on the association between job stress and workers' mental health, by removing the effects of unobserved time-invariant confounders. We used data from three to four waves of an occupational Japanese cohort survey, focusing on 31,382 observations of 9741 individuals who participated in at least two consecutive waves. We estimated mean-centered fixed effects models to explain psychological distress in terms of the Kessler 6 (K6) scores (range: 0-24) by eight job stress indicators related to the job demands-control, effort-reward imbalance, and organizational injustice models. Mean-centered fixed effects models reduced the magnitude of the association between jobs stress and K6 scores to 44.8-54.2% of those observed from pooled ordinary least squares. However, the association remained highly significant even after controlling for unobserved time-invariant confounders for all job stress indicators. In addition, alternatively specified models showed the robustness of the results. In all, we concluded that the validity of major job stress models, which link job stress and workers' mental health, was robust, although unobserved time-invariant confounders led to an overestimation of the association. Copyright © 2014 Elsevier Ltd. All rights reserved.

Epidemiologic studies of electric and magnetic fields and cancer: Strategies for extending knowledge

DOE Office of Scientific and Technical Information (OSTI.GOV)

Savitz, D.A.

1993-12-01

Epidemiologic research concerning electric and magnetic fields in relation to cancer has focused on the potential etiologic roles of residential exposure on childhood cancer and occupational exposure on adult leukemia and brain cancer. Future residential studies must concentrate on exposure assessment that is enhanced by developing models of historical exposure, assessment of the relation between magnetic fields and wire codes, and consideration of alternate exposure indices. Study design issues deserving attention include possible biases in random digit dialing control selection, consideration of the temporal course of exposure and disease, and acquisition of the necessary information to assess the potential valuemore » of ecologic studies. Highest priorities are comprehensive evaluation of exposure patterns and sources and examination of the sociology and geography of residential wire codes. Future occupational studies should also concentrate on improved exposure assessment with increased attention to nonutility worker populations and development of historical exposure indicators that are superior to job titles alone. Potential carcinogens in the workplace that could act as confounders need to be more carefully examined. The temporal relation between exposure and disease and possible effect modification by other workplace agents should be incorporated into future studies. The most pressing need is for measurement of exposure patterns in a variety of worker populations and performance of traditional epidemiologic evaluations of cancer occurrence. The principal source of bias toward the null is nondifferential misclassification of exposure with improvements expected to enhance any true etiologic association that is present. Biases away from the null might include biased control selection in residential studies and chemical carcinogens acting as confounders in occupational studies. 51 refs., 1 tab.« less

Sedentary Behavior and Mortality in Older Women

PubMed Central

Seguin, Rebecca; Buchner, David M.; Liu, Jingmin; Allison, Matthew; Manini, Todd; Wang, Ching-Yun; Manson, JoAnn E.; Messina, Catherine R.; Patel, Mahesh J.; Moreland, Larry; Stefanick, Marcia L.; LaCroix, Andrea Z.

2013-01-01

Background Although epidemiologic studies have shown associations between sedentary behavior and mortality, few have focused on older women with adequate minority representation and few have controlled for both physical activity and functional status. Purpose The objective of this study was to determine the relationship between sedentary time and total; cardiovascular disease (CVD); coronary heart disease (CHD); and cancer mortality in a prospective, multiethnic cohort of postmenopausal women. Methods The study population included 92,234 women aged 50–79 years at baseline (1993–1998) who participated in the Women’s Health Initiative Observational Study through September 2010. Self-reported sedentary time was assessed by questionnaire and examined in 4 categories (≤4, >4–8, ≥8–11, >11 hours). Mortality risks were examined using Cox proportional hazard models adjusting for confounders. Models were also stratified by age, race/ethnicity, body mass index, physical activity, physical function, and chronic disease to examine possible effect modification. Analyses were conducted in 2012–2013. Results The mean follow-up period was 12 years. Compared with women who reported the least sedentary time, women reporting the highest sedentary time had increased risk of all-cause mortality in the multivariate model (HR=1.12, 95% CI=1.05, 1.21). Results comparing the highest versus lowest categories for CVD, CHD, and cancer mortality were as follows: HR=1.13, 95% CI=0.99, 1.29; HR=1.27, 95% CI=1.04, 1.55; and HR=1.21, 95% CI=1.07, 1.37, respectively. For all mortality outcomes, there were significant linear tests for trend. Conclusions There was a linear relationship between greater amounts of sedentary time and mortality risk after controlling for multiple potential confounders. PMID:24439345

Vulnerability to extreme-heat-associated hospitalization in three counties in Michigan, USA, 2000–2009

PubMed Central

Ogbomo, Adesuwa S.; Gronlund, Carina J.; O’Neill, Marie S.; Konen, Tess; Cameron, Lorraine; Wahl, Robert

2016-01-01

Background With climate change, extreme heat (EH) events are increasing, so it is important to understand who is vulnerable to heat-associated morbidity. We determined the association between EH and hospitalizations for all natural causes, cardiovascular, respiratory, and renal diseases, diabetes mellitus, and acute myocardial infarction in Michigan, USA at different intensities and durations. We assessed confounding by ozone and how individual characteristics and health insurance payer (a proxy for income) modified these associations. Methods We obtained Michigan Inpatient Database, National Climatic Data Center, and U.S. Environmental Protection Agency ozone data for May–September, 2000–2009 for three Michigan counties. We employed a case-crossover design and modeled EH as an indicator for temperature above the 95th, 97th or 99th percentile thresholds for 1, 2, 3 or 4 days. We examined effect modification by patient age, race, sex, and health insurance payer and pooled the county results. Results Among non-whites, the pooled odds ratio for hospitalization on EH (97th-percentile threshold) vs. non-EH days for renal diseases was 1.37 (95% CI = 1.13–1.66), which increased with increasing EH intensity, but was null among whites (OR = 1.00, 95% CI = 0.81, 1.25). We observed a null association between EH and cardiovascular hospitalization. EH (99th-percentile threshold) was associated with myocardial infarction hospitalizations. Confounding by ozone was minimal. Conclusions EH was associated with hospitalizations for renal disease among non-whites. This information on vulnerability to heat-associated morbidity helps characterize the public health burden of EH and target interventions including patient education. PMID:27796569

[CONSUMPTION OF OMEGA- 3 FATTY ACIDS AND DEPRESSIVE SYMPTOMS IN COLLEGE STUDENTS FROM SONORA, MEXICO].

PubMed

Rubi Vargas, María; González Lomelí, Daniel; Terrazas Medina, Efraín A; Peralta Peña, Sandra L; Jordán Jinez, Ma Lourdes; Ruiz Paloalto, Ma Laura; Cupul Uicab, Lea A

2015-10-01

recent studies suggest that low serum levels of polyunsaturated fatty acids omega-3 are associated with a higher prevalence of depression. to evaluate whether low consumption of Omega-3 fatty acids is associated with a higher prevalence of depressive symptoms in a sample of college students from the Northwest of Mexico, and to assess the potential effect modification by alcohol consumption. we conducted a cross-sectional study in a sample of 706 college students (males and females) aged 18 to 24. The presence of depressive symptoms was identified with the Depression Scale of the Center for Epidemiologic Studies (CES-D), using a cutoff point of ≥ 24. The intake of omega-3 was obtained by a food frequency questionnaire validated for Mexican population. We estimated the weekly intake of alpha-linolenic fatty acid (ALA), eicosapentaenoic (EPA) and docosahexaenoic (DHA) derived from the diet in mg/g of food. The association between omega-3 from diet and the presence of depressive symptoms was assessed using logistic regression models adjusted for potential confounders. 67% of the participants were females; 16.6% were classified as having depressive symptoms. A low intake of ALA and EPA + DHA was not associated with depressive symptoms before and after adjusting for confounders. Median levels of ALA (from nuts only) were significantly lower among those with depressive symptoms compared to those without these symptoms. in this population of Mexican college students, a low intake of omega-3 fatty acids was not associated with depressive symptoms. The potential association between nut consumption and depressive symptoms deserve more attention. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Maternal asthma and transient tachypnea of the newborn.

PubMed

Demissie, K; Marcella, S W; Breckenridge, M B; Rhoads, G G

1998-07-01

To examine the relationship between transient tachypnea of the newborn and asthma complicating pregnancy. Historical cohort analysis. Setting. Singleton live deliveries in New Jersey hospitals during 1989 to 1992 (n = 447 963). Mother-infant dyads were identified from linked birth certificate and maternal and infant hospital claims data. Women with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis code (493) for asthma (n = 2289) were compared with a four-fold larger randomly selected control sample (n = 9156) from the remaining pool of women. Transient tachypnea of the newborn. In the overall sample, after controlling for the confounding effects of important variables, infants of asthmatic mothers were more likely [odds ratio (OR), 1. 79; 95% confidence interval (CI), 1.35-2.37] than infants of control mothers to exhibit transient tachypnea of the newborn. A stratified analysis by gestational age and sex revealed larger and statistically significant associations in term infants (OR, 2.02; 95% CI, 1.42-2.87) as opposed to preterm infants (OR, 1.51; 95% CI, 0.94-2.43) and in male infants (OR, 1.91; 95% CI, 1.35-2.71) as opposed to female infants (OR, 1.51; 95% CI, 0.92-2.47). On the other hand, after adjusting for important confounding variables, respiratory distress syndrome and maternal asthma were not found to be associated (OR, 1.14; 95% CI, 0.79-1.64). The results of this study provide evidence that maternal asthma is a risk factor for transient tachypnea of the newborn and differences in gestational age and sex were apparent in this association. The mechanism for this association remains to be determined.

Disability acquisition and mental health: effect modification by demographic and socioeconomic characteristics using data from an Australian longitudinal study.

PubMed

Aitken, Zoe; Simpson, Julie Anne; Bentley, Rebecca; Kavanagh, Anne Marie

2017-09-18

There is evidence of a causal relationship between disability acquisition and poor mental health, but the substantial heterogeneity in the magnitude of the effect is poorly understood and may be aetiologically informative. This study aimed to identify demographic and socioeconomic factors that modify the effect of disability acquisition on mental health. The Household, Income and Labour Dynamics in Australia Survey is a nationally representative longitudinal survey of Australian households that has been conducted annually since 2001. Four waves of data were included in this analysis, from 2011 to 2014. Individuals who acquired a disability (n=387) were compared with those who remained disability-free in all four waves (n=7936). Mental health was measured using the mental health subscale of the Short Form 36 (SF-36) general health questionnaire, which measures symptoms of depression, anxiety and psychological well-being. Linear regression models were fitted to estimate the effect of disability acquisition on mental health, testing for effect modification by key demographic and socioeconomic characteristics. To maximise causal inference, we used a propensity score approach with inverse probability of treatment weighting to control for confounding and multiple imputation using chained equations to assess the impact of missing data. On average, disability acquisition was associated with a 5-point decline in mental health score (estimated mean difference: -5.1, 95% CI -7.2 to -3.0). There was strong evidence that income and relationship status modified the effect, with more detrimental effects in the lowest (-12.5, 95% CI -18.5 to -6.5) compared with highest income quintile (-1.1, 95% CI -4.9 to 2.7) and for people not in a relationship (-8.8, 95% CI -12.9 to -4.8) compared with those who were (-3.7, 95% CI -6.1 to -1.4). Our results suggest that the detrimental effect of disability acquisition on mental health is substantially greater for socioeconomic disadvantaged individuals. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Everything that you have ever been told about assessment center ratings is confounded.

PubMed

Jackson, Duncan J R; Michaelides, George; Dewberry, Chris; Kim, Young-Jae

2016-07-01

Despite a substantial research literature on the influence of dimensions and exercises in assessment centers (ACs), the relative impact of these 2 sources of variance continues to raise uncertainties because of confounding. With confounded effects, it is not possible to establish the degree to which any 1 effect, including those related to exercises and dimensions, influences AC ratings. In the current study (N = 698) we used Bayesian generalizability theory to unconfound all of the possible effects contributing to variance in AC ratings. Our results show that ≤1.11% of the variance in AC ratings was directly attributable to behavioral dimensions, suggesting that dimension-related effects have no practical impact on the reliability of ACs. Even when taking aggregation level into consideration, effects related to general performance and exercises accounted for almost all of the reliable variance in AC ratings. The implications of these findings for recent dimension- and exercise-based perspectives on ACs are discussed. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Lack of effects on key cellular parameters of MRC-5 human lung fibroblasts exposed to 370 mT static magnetic field

NASA Astrophysics Data System (ADS)

Romeo, Stefania; Sannino, Anna; Scarfì, Maria Rosaria; Massa, Rita; D'Angelo, Raffaele; Zeni, Olga

2016-01-01

The last decades have seen increased interest toward possible adverse effects arising from exposure to intense static magnetic fields. This concern is mainly due to the wider and wider applications of such fields in industry and clinical practice; among them, Magnetic Resonance Imaging (MRI) facilities are the main sources of exposure to static magnetic fields for both general public (patients) and workers. In recent investigations, exposures to static magnetic fields have been demonstrated to elicit, in different cell models, both permanent and transient modifications in cellular endpoints critical for the carcinogenesis process. The World Health Organization has therefore recommended in vitro investigations as important research need, to be carried out under strictly controlled exposure conditions. Here we report on the absence of effects on cell viability, reactive oxygen species levels and DNA integrity in MRC-5 human foetal lung fibroblasts exposed to 370 mT magnetic induction level, under different exposure regimens. Exposures have been performed by using an experimental apparatus designed and realized for operating with the static magnetic field generated by permanent magnets, and confined in a magnetic circuit, to allow cell cultures exposure in absence of confounding factors like heating or electric field components.

The Shared Pathoetiological Effects of Particulate Air Pollution and the Social Environment on Fetal-Placental Development

PubMed Central

2014-01-01

Exposure to particulate air pollution and socioeconomic risk factors are shown to be independently associated with adverse pregnancy outcomes; however, their confounding relationship is an epidemiological challenge that requires understanding of their shared etiologic pathways affecting fetal-placental development. The purpose of this paper is to explore the etiological mechanisms associated with exposure to particulate air pollution in contributing to adverse pregnancy outcomes and how these mechanisms intersect with those related to socioeconomic status. Here we review the role of oxidative stress, inflammation and endocrine modification in the pathoetiology of deficient deep placentation and detail how the physical and social environments can act alone and collectively to mediate the established pathology linked to a spectrum of adverse pregnancy outcomes. We review the experimental and epidemiological literature showing that diet/nutrition, smoking, and psychosocial stress share similar pathways with that of particulate air pollution exposure to potentially exasperate the negative effects of either insult alone. Therefore, socially patterned risk factors often treated as nuisance parameters should be explored as potential effect modifiers that may operate at multiple levels of social geography. The degree to which deleterious exposures can be ameliorated or exacerbated via community-level social and environmental characteristics needs further exploration. PMID:25574176

Lack of effects on key cellular parameters of MRC-5 human lung fibroblasts exposed to 370 mT static magnetic field

PubMed Central

Romeo, Stefania; Sannino, Anna; Scarfì, Maria Rosaria; Massa, Rita; d’Angelo, Raffaele; Zeni, Olga

2016-01-01

The last decades have seen increased interest toward possible adverse effects arising from exposure to intense static magnetic fields. This concern is mainly due to the wider and wider applications of such fields in industry and clinical practice; among them, Magnetic Resonance Imaging (MRI) facilities are the main sources of exposure to static magnetic fields for both general public (patients) and workers. In recent investigations, exposures to static magnetic fields have been demonstrated to elicit, in different cell models, both permanent and transient modifications in cellular endpoints critical for the carcinogenesis process. The World Health Organization has therefore recommended in vitro investigations as important research need, to be carried out under strictly controlled exposure conditions. Here we report on the absence of effects on cell viability, reactive oxygen species levels and DNA integrity in MRC-5 human foetal lung fibroblasts exposed to 370 mT magnetic induction level, under different exposure regimens. Exposures have been performed by using an experimental apparatus designed and realized for operating with the static magnetic field generated by permanent magnets, and confined in a magnetic circuit, to allow cell cultures exposure in absence of confounding factors like heating or electric field components. PMID:26762783

Developing hazelnut tissue culture medium free of ion confounding

USDA-ARS?s Scientific Manuscript database

The general approach for tissue culture medium optimization is to use salts as factors in experimental design and analysis. However, using salts as factors leads to ion confounding, making it difficult to detect the effects of individual ions on particular growth responses. This study focused on tes...

Identification and Sensitivity Analysis for Average Causal Mediation Effects with Time-Varying Treatments and Mediators: Investigating the Underlying Mechanisms of Kindergarten Retention Policy.

PubMed

Park, Soojin; Steiner, Peter M; Kaplan, David

2018-06-01

Considering that causal mechanisms unfold over time, it is important to investigate the mechanisms over time, taking into account the time-varying features of treatments and mediators. However, identification of the average causal mediation effect in the presence of time-varying treatments and mediators is often complicated by time-varying confounding. This article aims to provide a novel approach to uncovering causal mechanisms in time-varying treatments and mediators in the presence of time-varying confounding. We provide different strategies for identification and sensitivity analysis under homogeneous and heterogeneous effects. Homogeneous effects are those in which each individual experiences the same effect, and heterogeneous effects are those in which the effects vary over individuals. Most importantly, we provide an alternative definition of average causal mediation effects that evaluates a partial mediation effect; the effect that is mediated by paths other than through an intermediate confounding variable. We argue that this alternative definition allows us to better assess at least a part of the mediated effect and provides meaningful and unique interpretations. A case study using ECLS-K data that evaluates kindergarten retention policy is offered to illustrate our proposed approach.

Residential proximity to electromagnetic field sources and birth weight: Minimizing residual confounding using multiple imputation and propensity score matching.

PubMed

de Vocht, Frank; Lee, Brian

2014-08-01

Studies have suggested that residential exposure to extremely low frequency (50 Hz) electromagnetic fields (ELF-EMF) from high voltage cables, overhead power lines, electricity substations or towers are associated with reduced birth weight and may be associated with adverse birth outcomes or even miscarriages. We previously conducted a study of 140,356 singleton live births between 2004 and 2008 in Northwest England, which suggested that close residential proximity (≤ 50 m) to ELF-EMF sources was associated with reduced average birth weight of 212 g (95%CI: -395 to -29 g) but not with statistically significant increased risks for other adverse perinatal outcomes. However, the cohort was limited by missing data for most potentially confounding variables including maternal smoking during pregnancy, which was only available for a small subgroup, while also residual confounding could not be excluded. This study, using the same cohort, was conducted to minimize the effects of these problems using multiple imputation to address missing data and propensity score matching to minimize residual confounding. Missing data were imputed using multiple imputation using chained equations to generate five datasets. For each dataset 115 exposed women (residing ≤ 50 m from a residential ELF-EMF source) were propensity score matched to 1150 unexposed women. After doubly robust confounder adjustment, close proximity to a residential ELF-EMF source remained associated with a reduction in birth weight of -116 g (95% confidence interval: -224:-7 g). No effect was found for proximity ≤ 100 m compared to women living further away. These results indicate that although the effect size was about half of the effect previously reported, close maternal residential proximity to sources of ELF-EMF remained associated with suboptimal fetal growth. Copyright © 2014 Elsevier Ltd. All rights reserved.

On Estimation of the Survivor Average Causal Effect in Observational Studies when Important Confounders are Missing Due to Death

PubMed Central

Egleston, Brian L.; Scharfstein, Daniel O.; MacKenzie, Ellen

2008-01-01

We focus on estimation of the causal effect of treatment on the functional status of individuals at a fixed point in time t* after they have experienced a catastrophic event, from observational data with the following features: (1) treatment is imposed shortly after the event and is non-randomized, (2) individuals who survive to t* are scheduled to be interviewed, (3) there is interview non-response, (4) individuals who die prior to t* are missing information on pre-event confounders, (5) medical records are abstracted on all individuals to obtain information on post-event, pre-treatment confounding factors. To address the issue of survivor bias, we seek to estimate the survivor average causal effect (SACE), the effect of treatment on functional status among the cohort of individuals who would survive to t* regardless of whether or not assigned to treatment. To estimate this effect from observational data, we need to impose untestable assumptions, which depend on the collection of all confounding factors. Since pre-event information is missing on those who die prior to t*, it is unlikely that these data are missing at random (MAR). We introduce a sensitivity analysis methodology to evaluate the robustness of SACE inferences to deviations from the MAR assumption. We apply our methodology to the evaluation of the effect of trauma center care on vitality outcomes using data from the National Study on Costs and Outcomes of Trauma Care. PMID:18759833

Short-term effects of air pollution on daily hospital admissions for cardiovascular diseases in western China.

PubMed

Ma, Yuxia; Zhang, Haipeng; Zhao, Yuxin; Zhou, Jianding; Yang, Sixu; Zheng, Xiaodong; Wang, Shigong

2017-06-01

Controlling the confounding factors on cardiovascular diseases, such as long-time trend, calendar effect, and meteorological factors, a generalized additive model (GAM) was used to investigate the short-term effects of air pollutants (PM 10 , SO 2 , and NO 2 ) on daily cardiovascular admissions from March 1st to May 31st during 2007 to 2011 in Lanzhou, a heavily polluted city in western China. The influences of air pollutants were examined with different lag structures, and the potential effect modification by dust storm in spring was also investigated. Significant associations were found between air pollutants and hospital admissions for cardiovascular diseases both on dust event days and non-dust event days in spring. Air pollutants had lag effects on different age and gender groups. Relative risks (RRs) and their 95% confidence intervals (CIs) associated with a 10 μg/m 3 increase were 1.14 (1.04~1.26) on lag1 for PM 10 , 1.31 (1.21~1.51) on lag01 for SO 2 , and 1.96 (1.49~2.57) on lag02 for NO 2 on dust days. Stronger effects of air pollutants were observed for females and the elderly (≥60 years). Our analysis concluded that the effects of air pollutants on cardiovascular admissions on dust days were significantly stronger than non-dust days. The current study strengthens the evidence of effects of air pollution on health and dust-exacerbated cardiovascular admissions in Lanzhou.

The Value of Response Times in Item Response Modeling

ERIC Educational Resources Information Center

Molenaar, Dylan

2015-01-01

A new and very interesting approach to the analysis of responses and response times is proposed by Goldhammer (this issue). In his approach, differences in the speed-ability compromise within respondents are considered to confound the differences in ability between respondents. These confounding effects of speed on the inferences about ability can…

Role of associated mineral fibres in chrysotile asbestos health effects: the case of balangeroite.

PubMed

Turci, Francesco; Tomatis, Maura; Compagnoni, Roberto; Fubini, Bice

2009-07-01

To evaluate the biodurability of balangeroite, present as contaminant of chrysotile asbestos in the Balangero mine, in order to have indication whether it might have been a confounding factor in the association of the mesothelioma cases reported among mine workers and employees. The modifications taking place following incubation of the fibres in simulated phagolysosomal fluids have been measured on balangeroite, on one pure chrysotile sample (Val Malenco), on one chrysotile from Balangero with some associated balangeroite, and on two tremolite samples. The incubation modifies both chrysotile and balangeroite with substantial release in the medium of the metal ions which occupy the octahedral site in the mineral structure of the fibre while tremolite is virtually unaffected. Considering the profound differences between the structure of balangeroite and amphiboles, previous results and observations on the poor ecopersistence of balangeroite, and the present data, we conclude that balangeroite traces may contribute to the overall toxicity of the airborne fibres in Balangero, but may not be compared to tremolite nor considered the sole responsible for the excess of mesothelioma found in Balangero.

Combating Unmeasured Confounding in Cross-Sectional Studies: Evaluating Instrumental-Variable and Heckman Selection Models

PubMed Central

DeMaris, Alfred

2014-01-01

Unmeasured confounding is the principal threat to unbiased estimation of treatment “effects” (i.e., regression parameters for binary regressors) in nonexperimental research. It refers to unmeasured characteristics of individuals that lead them both to be in a particular “treatment” category and to register higher or lower values than others on a response variable. In this article, I introduce readers to 2 econometric techniques designed to control the problem, with a particular emphasis on the Heckman selection model (HSM). Both techniques can be used with only cross-sectional data. Using a Monte Carlo experiment, I compare the performance of instrumental-variable regression (IVR) and HSM to that of ordinary least squares (OLS) under conditions with treatment and unmeasured confounding both present and absent. I find HSM generally to outperform IVR with respect to mean-square-error of treatment estimates, as well as power for detecting either a treatment effect or unobserved confounding. However, both HSM and IVR require a large sample to be fully effective. The use of HSM and IVR in tandem with OLS to untangle unobserved confounding bias in cross-sectional data is further demonstrated with an empirical application. Using data from the 2006–2010 General Social Survey (National Opinion Research Center, 2014), I examine the association between being married and subjective well-being. PMID:25110904

Sleep Duration and Overweight in European Children: Is the Association Modified by Geographic Region?

PubMed Central

Hense, Sabrina; Pohlabeln, Hermann; De Henauw, Stefaan; Eiben, Gabriele; Molnar, Dénes; Moreno, Luis A.; Barba, Gianvincenzo; Hadjigeorgiou, Charalampos; Veidebaum, Toomas; Ahrens, Wolfgang

2011-01-01

Study Objectives: To investigate differences and a possible effect modification by geographical region in the association between sleep duration and overweight. Design: Cross-sectional. Setting: Primary schools and preschools in 8 European countries. Participants: 7867 children aged 2 to 9 years. Interventions: Not applicable. Measurements: Nocturnal sleep duration was assessed as part of a parental 24-h recall. Height and weight were measured by standardized procedures across centers. Data on personal, social, environmental and behavioral factors were collected using a standardized parental questionnaire. Results: Sleep duration differed (P < 0.001) between European regions and normal vs. overweight children. A dose-dependent inverse association between sleep duration and overweight could be seen, with crude odds ratios ranging from 1.73 (99% CI 1.33; 2.25) for sleeping between 10 and 11 h to 3.81 (99% CI 2.85; 5.09) for sleeping less than 9 h (reference category > 11 h). This persisted after adjustment, but remained significant only for sleeping less than 9 h per night (north: OR = 1.70; 99% CI 1.13; 2.58 vs. south: OR = 2.84; 99% CI 1.57; 5.12) if stratified by region. No effect modification by region could be found, but adjustment for region accounted for changes in the effect estimate for sleeping less than 9 h (OR = 2.22; 99% CI 1.64; 3.02). The association was stronger in school children than in preschool children. Conclusion: Geographic region and related aspects—even if they do not seem to modify the association between sleep and overweight—should in any case be taken in consideration as a confounding factor on this association. Citation: Hense S; Pohlabeln H; De Henauw S; Eiben G; Molnar D; Moreno LA; Barba G; Hadjigeorgiou C; Veidebaum T; Ahrens W. Sleep duration and overweight in European children: is the association modified by geographic region? SLEEP 2011;34(7):885-890. PMID:21731138

Procedural Factors That Affect Psychophysical Measures of Spatial Selectivity in Cochlear Implant Users

PubMed Central

Deeks, John M.; Carlyon, Robert P.

2015-01-01

Behavioral measures of spatial selectivity in cochlear implants are important both for guiding the programing of individual users’ implants and for the evaluation of different stimulation methods. However, the methods used are subject to a number of confounding factors that can contaminate estimates of spatial selectivity. These factors include off-site listening, charge interactions between masker and probe pulses in interleaved masking paradigms, and confusion effects in forward masking. We review the effects of these confounds and discuss methods for minimizing them. We describe one such method in which the level of a 125-pps masker is adjusted so as to mask a 125-pps probe, and where the masker and probe pulses are temporally interleaved. Five experiments describe the method and evaluate the potential roles of the different potential confounding factors. No evidence was obtained for off-site listening of the type observed in acoustic hearing. The choice of the masking paradigm was shown to alter the measured spatial selectivity. For short gaps between masker and probe pulses, both facilitation and refractory mechanisms had an effect on masking; this finding should inform the choice of stimulation rate in interleaved masking experiments. No evidence for confusion effects in forward masking was revealed. It is concluded that the proposed method avoids many potential confounds but that the choice of method should depend on the research question under investigation. PMID:26420785

Comparing a marginal structural model with a Cox proportional hazard model to estimate the effect of time-dependent drug use in observational studies: statin use for primary prevention of cardiovascular disease as an example from the Rotterdam Study.

PubMed

de Keyser, Catherine E; Leening, Maarten J G; Romio, Silvana A; Jukema, J Wouter; Hofman, Albert; Ikram, M Arfan; Franco, Oscar H; Stijnen, Theo; Stricker, Bruno H

2014-11-01

When studying the causal effect of drug use in observational data, marginal structural modeling (MSM) can be used to adjust for time-dependent confounders that are affected by previous treatment. The objective of this study was to compare traditional Cox proportional hazard models (with and without time-dependent covariates) with MSM to study causal effects of time-dependent drug use. The example of primary prevention of cardiovascular disease (CVD) with statins was examined using up to 17.7 years of follow-up from 4,654 participants of the observational prospective population-based Rotterdam Study. In the MSM model, the weight was based on measurements of established cardiovascular risk factors and co-morbidity. In general, we could not demonstrate important differences in results from the Cox models and MSM. Results from analysis on duration of statin use suggested that substantial residual confounding by indication was not accounted for during the period shortly after statin initiation. In conclusion, although on theoretical grounds MSM is an elegant technique, lack of data on the precise time-dependent confounders, such as indication of treatment or other considerations of the prescribing physician jeopardizes the calculation of valid weights. Confounding remains a hurdle in observational effectiveness research on preventive drugs with a multitude of prescription determinants.

Advanced statistical methods to study the effects of gastric tube and non-invasive ventilation on functional decline and survival in amyotrophic lateral sclerosis.

PubMed

Atassi, Nazem; Cudkowicz, Merit E; Schoenfeld, David A

2011-07-01

A few studies suggest that non-invasive ventilation (1) and gastric tube (G-tube) may have a positive impact on survival but the effect on functional decline is unclear. Confounding by indication may have produced biased estimates of the benefit seen in some of these retrospective studies. The objective of this study was to evaluate the effects of G-tube and NIV on survival and functional decline using advanced statistical models that adjust for confounding by indications. A database of 331 subjects enrolled in previous clinical trials in ALS was available for analysis. Marginal structural models (MSM) were used to compare the mortality hazards and ALSFRS-R slopes between treatment and non-treatment groups, after adjusting for confounding by indication. Results showed that the placement of a G-tube was associated with an additional 1.42 units/month decline in the ALSFRS-R slope (p < 0.0001) and increased mortality hazard of 0.28 (p = 0.02). The use of NIV had no significant effect on ALSFRS-R decline or mortality. In conclusion, marginal structural models can be used to adjust for confounding by indication in retrospective ALS studies. G-tube placement could be followed by a faster rate of functional decline and increased mortality. Our results may suffer from some of the limitations of retrospective analyses.

How multiple causes combine: independence constraints on causal inference.

PubMed

Liljeholm, Mimi

2015-01-01

According to the causal power view, two core constraints-that causes occur independently (i.e., no confounding) and influence their effects independently-serve as boundary conditions for causal induction. This study investigated how violations of these constraints modulate uncertainty about the existence and strength of a causal relationship. Participants were presented with pairs of candidate causes that were either confounded or not, and that either interacted or exerted their influences independently. Consistent with the causal power view, uncertainty about the existence and strength of causal relationships was greater when causes were confounded or interacted than when unconfounded and acting independently. An elemental Bayesian causal model captured differences in uncertainty due to confounding but not those due to an interaction. Implications of distinct sources of uncertainty for the selection of contingency information and causal generalization are discussed.

Maternal nicotine exposure effects on adolescent learning and memory are abolished in alpha(α)2* nicotinic acetylcholine receptor-null mutant mice.

PubMed

Mojica, Celina; Bai, Yu; Lotfipour, Shahrdad

2018-06-01

The objective of the current study is to test the hypothesis that the deletion of alpha(α)2* nicotinic acetylcholine receptors (nAChRs) (encoded by the Chrna2 gene) ablate maternal nicotine-induced learning and memory deficits in adolescent mice. We use a pre-exposure-dependent contextual fear conditioning behavioral paradigm that is highly hippocampus-dependent. Adolescent wild type and α2-null mutant offspring are exposed to vehicle or maternal nicotine exposure (200 μg/ml, expressed as base) in the drinking water throughout pregnancy until weaning. Adolescent male offspring mice are tested for alterations in growth and development characteristics as well as modifications in locomotion, anxiety, shock-reactivity and learning and memory. As expected, maternal nicotine exposure has no effects on pup number, weight gain and only modestly reduces fluid intake by 19%. Behaviorally, maternal nicotine exposure impedes extinction learning in adolescent wild type mice, a consequence that is abolished in α2-null mutant mice. The effects on learning and memory are not confounded by alternations in stereotypy, locomotion, anxiety or sensory shock reactivity. Overall, the findings highlight that the deletion of α2* nAChRs eliminate the effects of maternal nicotine exposure on learning and memory in adolescent mice. Copyright © 2018 Elsevier Ltd. All rights reserved.

Longitudinal trends of total white blood cell and differential white blood cell counts of atomic bomb survivors.

PubMed

Hsu, Wan-Ling; Tatsukawa, Yoshimi; Neriishi, Kazuo; Yamada, Michiko; Cologne, John; Fujiwara, Saeko

2010-01-01

In studying the late health effects of atomic-bomb (A-bomb) survivors, earlier findings were that white blood cell (WBC) count increased with radiation dose in cross-sectional studies. However, a persistent effect of radiation on WBC count and other risk factors has yet to be confirmed. The objectives of the present study were 1) to examine the longitudinal relationship between A-bomb radiation dose and WBC and differential WBC counts among A-bomb survivors and 2) to investigate the potential confounding risk factors (such as age at exposure and smoking status) as well as modification of the radiation dose-response. A total of 7,562 A-bomb survivors in Hiroshima and Nagasaki were included in this study from 1964-2004. A linear mixed model was applied using the repeated WBC measurements. During the study period, a secular downward trend of WBC count was observed. Radiation exposure was a significant risk factor for elevated WBC and differential WBC counts over time. A significant increase of WBC counts among survivors with high radiation dose (> 2 Gy) was detected in men exposed below the age of 20 and in women regardless of age at exposure. Effects on WBC of low dose radiation remain unclear, however. Cigarette smoking produced the most pronounced effect on WBC counts and its impact was much larger than that of radiation exposure.

Exogenous factors matter when interpreting the results of an impact evaluation: a case study of rainfall and child health programme intervention in Rwanda.

PubMed

Mukabutera, Assumpta; Thomson, Dana R; Hedt-Gauthier, Bethany L; Atwood, Sidney; Basinga, Paulin; Nyirazinyoye, Laetitia; Savage, Kevin P; Habimana, Marcellin; Murray, Megan

2017-12-01

Public health interventions are often implemented at large scale, and their evaluation seems to be difficult because they are usually multiple and their pathways to effect are complex and subject to modification by contextual factors. We assessed whether controlling for rainfall-related variables altered estimates of the efficacy of a health programme in rural Rwanda and have a quantifiable effect on an intervention evaluation outcomes. We conducted a retrospective quasi-experimental study using previously collected cross-sectional data from the 2005 and 2010 Rwanda Demographic and Health Surveys (DHS), 2010 DHS oversampled data, monthly rainfall data collected from meteorological stations over the same period, and modelled output of long-term rainfall averages, soil moisture, and rain water run-off. Difference-in-difference models were used. Rainfall factors confounded the PIH intervention impact evaluation. When we adjusted our estimates of programme effect by controlling for a variety of rainfall variables, several effectiveness estimates changed by 10% or more. The analyses that did not adjust for rainfall-related variables underestimated the intervention effect on the prevalence of ARI by 14.3%, fever by 52.4% and stunting by 10.2%. Conversely, the unadjusted analysis overestimated the intervention's effect on diarrhoea by 56.5% and wasting by 80%. Rainfall-related patterns have a quantifiable effect on programme evaluation results and highlighted the importance and complexity of controlling for contextual factors in quasi-experimental design evaluations. © 2017 John Wiley & Sons Ltd.

An analysis of heat effects in different subpopulations of Bangladesh

NASA Astrophysics Data System (ADS)

Burkart, Katrin; Breitner, Susanne; Schneider, Alexandra; Khan, Md. Mobarak Hossain; Krämer, Alexander; Endlicher, Wilfried

2014-03-01

A substantial number of epidemiological studies have demonstrated an association between atmospheric conditions and human all-cause as well as cause-specific mortality. However, most research has been performed in industrialised countries, whereas little is known about the atmosphere-mortality relationship in developing countries. Especially with regard to modifications from non-atmospheric conditions and intra-population differences, there is a substantial research deficit. Within the scope of this study, we aimed to investigate the effects of heat in a multi-stratified manner, distinguishing by the cause of death, age, gender, location and socio-economic status. We examined 22,840 death counts using semi-parametric Poisson regression models, adjusting for a multitude of potential confounders. Although Bangladesh is dominated by an increase of mortality with decreasing (equivalent) temperatures over a wide range of values, the findings demonstrated the existence of partly strong heat effects at the upper end of the temperature distribution. Moreover, the study demonstrated that the strength of these heat effects varied considerably over the investigated subgroups. The adverse effects of heat were particularly pronounced for males and the elderly above 65 years. Moreover, we found increased adverse effects of heat for urban areas and for areas with a high socio-economic status. The increase in, and acceleration of, urbanisation in Bangladesh, as well as the rapid aging of the population and the increase in non-communicable diseases, suggest that the relevance of heat-related mortality might increase further. Considering rising global temperatures, the adverse effects of heat might be further aggravated.

Mediation and moderation of treatment effects in randomised controlled trials of complex interventions.

PubMed

Emsley, Richard; Dunn, Graham; White, Ian R

2010-06-01

Complex intervention trials should be able to answer both pragmatic and explanatory questions in order to test the theories motivating the intervention and help understand the underlying nature of the clinical problem being tested. Key to this is the estimation of direct effects of treatment and indirect effects acting through intermediate variables which are measured post-randomisation. Using psychological treatment trials as an example of complex interventions, we review statistical methods which crucially evaluate both direct and indirect effects in the presence of hidden confounding between mediator and outcome. We review the historical literature on mediation and moderation of treatment effects. We introduce two methods from within the existing causal inference literature, principal stratification and structural mean models, and demonstrate how these can be applied in a mediation context before discussing approaches and assumptions necessary for attaining identifiability of key parameters of the basic causal model. Assuming that there is modification by baseline covariates of the effect of treatment (i.e. randomisation) on the mediator (i.e. covariate by treatment interactions), but no direct effect on the outcome of these treatment by covariate interactions leads to the use of instrumental variable methods. We describe how moderation can occur through post-randomisation variables, and extend the principal stratification approach to multiple group methods with explanatory models nested within the principal strata. We illustrate the new methodology with motivating examples of randomised trials from the mental health literature.

Accounting for context in studies of health inequalities: a review and comparison of analytic approaches.

PubMed

Schempf, Ashley H; Kaufman, Jay S

2012-10-01

A common epidemiologic objective is to evaluate the contribution of residential context to individual-level disparities by race or socioeconomic position. We reviewed analytic strategies to account for the total (observed and unobserved factors) contribution of environmental context to health inequalities, including conventional fixed effects (FE) and hybrid FE implemented within a random effects (RE) or a marginal model. To illustrate results and limitations of the various analytic approaches of accounting for the total contextual component of health disparities, we used data on births nested within neighborhoods as an applied example of evaluating neighborhood confounding of racial disparities in gestational age at birth, including both a continuous and a binary outcome. Ordinary and RE models provided disparity estimates that can be substantially biased in the presence of neighborhood confounding. Both FE and hybrid FE models can account for cluster level confounding and provide disparity estimates unconfounded by neighborhood, with the latter having greater flexibility in allowing estimation of neighborhood-level effects and intercept/slope variability when implemented in a RE specification. Given the range of models that can be implemented in a hybrid approach and the frequent goal of accounting for contextual confounding, this approach should be used more often. Published by Elsevier Inc.

Breast feeding and resilience against psychosocial stress.

PubMed

Montgomery, S M; Ehlin, A; Sacker, A

2006-12-01

Some early life exposures may result in a well controlled stress response, which can reduce stress related anxiety. Breast feeding may be a marker of some relevant exposures. To assess whether breast feeding is associated with modification of the relation between parental divorce and anxiety. Observational study using longitudinal birth cohort data. Linear regression was used to assess whether breast feeding modifies the association of parental divorce/separation with anxiety using stratification and interaction testing. Data were obtained from the 1970 British Cohort Study, which is following the lives of those born in one week in 1970 and living in Great Britain. This study uses information collected at birth and at ages 5 and 10 years for 8958 subjects. Class teachers answered a question on anxiety among 10 year olds using an analogue scale (range 0-50) that was log transformed to minimise skewness. Among 5672 non-breast fed subjects, parental divorce/separation was associated with a statistically significantly raised risk of anxiety, with a regression coefficient (95% CI) of 9.4 (6.1 to 12.8). Among the breast fed group this association was much lower: 2.2 (-2.6 to 7.0). Interaction testing confirmed statistically significant effect modification by breast feeding, independent of simultaneous adjustment for multiple potential confounding factors, producing an interaction coefficient of -7.0 (-12.8 to -1.2), indicating a 7% reduction in anxiety after adjustment. Breast feeding is associated with resilience against the psychosocial stress linked with parental divorce/separation. This could be because breast feeding is a marker of exposures related to maternal characteristics and parent-child interaction.

Natural flow regimes, nonnative fishes, and native fish persistence in arid-land river systems.

PubMed

Propst, David L; Gido, Keith B; Stefferud, Jerome A

2008-07-01

Escalating demands for water have led to substantial modifications of river systems in arid regions, which coupled with the widespread invasion of nonnative organisms, have increased the vulnerability of native aquatic species to extirpation. Whereas a number of studies have evaluated the role of modified flow regimes and nonnative species on native aquatic assemblages, few have been conducted where the compounding effects of modified flow regimes and established nonnatives do not confound interpretations, particularly at spatial and temporal scales that are relevant to conservation of species at a range-wide level. By evaluating a 19-year data set across six sites in the relatively unaltered upper Gila River basin, New Mexico, USA, we tested how natural flow regimes and presence of nonnative species affected long-term stability of native fish assemblages. Overall, we found that native fish density was greatest during a wet period at the beginning of our study and declined during a dry period near the end of the study. Nonnative fishes, particularly predators, generally responded in opposite directions to these climatic cycles. Our data suggested that chronic presence of nonnative fishes, coupled with naturally low flows reduced abundance of individual species and compromised persistence of native fish assemblages. We also found that a natural flow regime alone was unlikely to ensure persistence of native fish assemblages. Rather, active management that maintains natural flow regimes while concurrently suppressing or excluding nonnative fishes from remaining native fish strongholds is critical to conservation of native fish assemblages in a system, such as the upper Gila River drainage, with comparatively little anthropogenic modification.

Salmonella enterica Serovar Typhi Lipopolysaccharide O-Antigen Modification Impact on Serum Resistance and Antibody Recognition

DOE PAGES

Kintz, Erica; Heiss, Christian; Black, Ian; ...

2017-02-06

Salmonella enterica serovar Typhi is a human-restricted Gram-negative bacterial pathogen responsible for causing an estimated 27 million cases of typhoid fever annually, leading to 217,000 deaths, and current vaccines do not offer full protection. The O-antigen side chain of the lipopolysaccharide is an immunodominant antigen, can define host-pathogen interactions, and is under consideration as a vaccine target for some Gram-negative species. The composition of the O-antigen can be modified by the activity of glycosyltransferase (gtr) operons acquired by horizontal gene transfer. Here we investigate the role of two gtr operons that we identified in the S. Typhi genome. Strains weremore » engineered to express specific gtr operons. Full chemical analysis of the O-antigens of these strains identified gtr-dependent glucosylation and acetylation. The glucosylated form of the O-antigen mediated enhanced survival in human serum and decreased complement binding. A single nucleotide deviation from an epigenetic phase variation signature sequence rendered the expression of this glucosylating gtr operon uniform in the population. In contrast, the expression of the acetylating gtrC gene is controlled by epigenetic phase variation. Acetylation did not affect serum survival, but phase variation can be an immune evasion mechanism, and thus, this modification may contribute to persistence in a host. In murine immunization studies, both O-antigen modifications were generally immunodominant. Our results emphasize that natural O-antigen modifications should be taken into consideration when assessing responses to vaccines, especially O-antigen-based vaccines, and that the Salmonella gtr repertoire may confound the protective efficacy of broad-ranging Salmonella lipopolysaccharide conjugate vaccines.« less

Salmonella enterica Serovar Typhi Lipopolysaccharide O-Antigen Modification Impact on Serum Resistance and Antibody Recognition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kintz, Erica; Heiss, Christian; Black, Ian

Salmonella enterica serovar Typhi is a human-restricted Gram-negative bacterial pathogen responsible for causing an estimated 27 million cases of typhoid fever annually, leading to 217,000 deaths, and current vaccines do not offer full protection. The O-antigen side chain of the lipopolysaccharide is an immunodominant antigen, can define host-pathogen interactions, and is under consideration as a vaccine target for some Gram-negative species. The composition of the O-antigen can be modified by the activity of glycosyltransferase (gtr) operons acquired by horizontal gene transfer. Here we investigate the role of two gtr operons that we identified in the S. Typhi genome. Strains weremore » engineered to express specific gtr operons. Full chemical analysis of the O-antigens of these strains identified gtr-dependent glucosylation and acetylation. The glucosylated form of the O-antigen mediated enhanced survival in human serum and decreased complement binding. A single nucleotide deviation from an epigenetic phase variation signature sequence rendered the expression of this glucosylating gtr operon uniform in the population. In contrast, the expression of the acetylating gtrC gene is controlled by epigenetic phase variation. Acetylation did not affect serum survival, but phase variation can be an immune evasion mechanism, and thus, this modification may contribute to persistence in a host. In murine immunization studies, both O-antigen modifications were generally immunodominant. Our results emphasize that natural O-antigen modifications should be taken into consideration when assessing responses to vaccines, especially O-antigen-based vaccines, and that the Salmonella gtr repertoire may confound the protective efficacy of broad-ranging Salmonella lipopolysaccharide conjugate vaccines.« less

Tutorial in Biostatistics: Instrumental Variable Methods for Causal Inference*

PubMed Central

Baiocchi, Michael; Cheng, Jing; Small, Dylan S.

2014-01-01

A goal of many health studies is to determine the causal effect of a treatment or intervention on health outcomes. Often, it is not ethically or practically possible to conduct a perfectly randomized experiment and instead an observational study must be used. A major challenge to the validity of observational studies is the possibility of unmeasured confounding (i.e., unmeasured ways in which the treatment and control groups differ before treatment administration which also affect the outcome). Instrumental variables analysis is a method for controlling for unmeasured confounding. This type of analysis requires the measurement of a valid instrumental variable, which is a variable that (i) is independent of the unmeasured confounding; (ii) affects the treatment; and (iii) affects the outcome only indirectly through its effect on the treatment. This tutorial discusses the types of causal effects that can be estimated by instrumental variables analysis; the assumptions needed for instrumental variables analysis to provide valid estimates of causal effects and sensitivity analysis for those assumptions; methods of estimation of causal effects using instrumental variables; and sources of instrumental variables in health studies. PMID:24599889

An assessment of the possible extent of confounding in epidemiological studies of lung cancer risk among roofers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mundt, D.J.; van Wijngaarden, E.; Mundt, K.A.

2007-07-01

We evaluated the likelihood and extent to which the observed increased risk of lung cancer may be due to confounding (a mixing of effects of multiple exposures) by co-exposure to other potential carcinogens present in roofing or to lifestyle variables. We conducted a review of the epidemiological and industrial hygiene literature of asphalt-exposed workers. Peer-reviewed epidemiological studies of asphalt fumes, related occupational exposures, and confounding factors were identified from MEDLINE (1966 early 2004). Industrial hygiene studies of asphalt workers were identified through MEDLINE, publicly available government documents, and asphalt industry documents. Using well established statistical methods, we quantified the extentmore » to which lung cancer relative risk estimates among roofers reflect confounding from other exposures, using different prevalence and risk scenarios. The relative risk of lung cancer varied from 1.2 to 5.0 in 13 epidemiological studies of roofers; most studies reported a relative risk between 1.2 and 1.4. Smoking, asbestos and coal tar were the most likely confounders, but the prevalence of these factors varied over time. The results of the study indicate that much of the observed risk reported in epidemiological studies of cancer among roofers is well within the range of what may have resulted from confounding by reasonable and expected levels of smoking, asbestos or coal tar. This may be particularly true for those studies that did not adjust for these confounders and where the exposure was defined as employment in the roofing industry. In addition to poorly defined asphalt exposure, uncontrolled confounding cannot reliably be ruled out in studies of lung cancer among asphalt-exposed roofers. Therefore, it is not possible to conclude whether roofers are at increased risk of lung cancer due to asphalt exposure.« less

Weight Loss and Coronary Heart Disease: Sensitivity Analysis for Unmeasured Confounding by Undiagnosed Disease.

PubMed

Danaei, Goodarz; Robins, James M; Young, Jessica G; Hu, Frank B; Manson, JoAnn E; Hernán, Miguel A

2016-03-01

Evidence for the effect of weight loss on coronary heart disease (CHD) or mortality has been mixed. The effect estimates can be confounded due to undiagnosed diseases that may affect weight loss. We used data from the Nurses' Health Study to estimate the 26-year risk of CHD under several hypothetical weight loss strategies. We applied the parametric g-formula and implemented a novel sensitivity analysis for unmeasured confounding due to undiagnosed disease by imposing a lag time for the effect of weight loss on chronic disease. Several sensitivity analyses were conducted. The estimated 26-year risk of CHD did not change under weight loss strategies using lag times from 0 to 18 years. For a 6-year lag time, the risk ratios of CHD for weight loss compared with no weight loss ranged from 1.00 (0.99, 1.02) to 1.02 (0.99, 1.05) for different degrees of weight loss with and without restricting the weight loss strategy to participants with no major chronic disease. Similarly, no protective effect of weight loss was estimated for mortality risk. In contrast, we estimated a protective effect of weight loss on risk of type 2 diabetes. We estimated that maintaining or losing weight after becoming overweight or obese does not reduce the risk of CHD or death in this cohort of middle-age US women. Unmeasured confounding, measurement error, and model misspecification are possible explanations but these did not prevent us from estimating a beneficial effect of weight loss on diabetes.

A step towards understanding the mechanisms of running-related injuries.

PubMed

Malisoux, Laurent; Nielsen, Rasmus Oestergaard; Urhausen, Axel; Theisen, Daniel

2015-09-01

To investigate the association between training-related characteristics and running-related injury using a new conceptual model for running-related injury generation, focusing on the synergy between training load and previous injuries, short-term running experience or body mass index (> or < 25 kg m(-2)). Prospective cohort study with a 9-month follow-up. The data of two previous studies using the same methodology were revisited. Recreational runners (n = 517) reported information about running training characteristics (weekly distance, frequency, speed), other sport participation and injuries on a dedicated internet platform. Weekly volume (dichotomized into < 2h and ≥ 2 h) and session frequency (dichotomized into < 2 and ≥ 2) were the main exposures because they were considered necessary causes for running-related injury. Non-training-related characteristics were included in Cox regression analyses as effect-measure modifiers. Hazard ratio was the measure of association. The size of effect-measure modification was calculated as the relative excess risk due to interaction. One hundred sixty-seven runners reported a running-related injury. Crude analyses revealed that weekly volume < 2h (hazard ratio = 3.29; 95% confidence intervals = 2.27; 4.79) and weekly session frequency < 2 (hazard ratio = 2.41; 95% confidence intervals = 1.71; 3.42) were associated with increased injury rate. Previous injury was identified as an effect-measure modifier on weekly volume (relative excess risk due to interaction = 4.69; 95% confidence intervals = 1.42; 7.95; p = 0.005) and session frequency (relative excess risk due to interaction = 2.44; 95% confidence intervals = 0.48; 4.39; p = 0.015). A negative synergy was found between body mass index and weekly volume (relative excess risk due to interaction = -2.88; 95% confidence intervals = -5.10; -0.66; p = 0.018). The effect of a runner's training load on running-related injury is influenced by body mass index and previous injury. These results show the importance to distinguish between confounding and effect-measure modification in running-related injury research. Copyright © 2014 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

Short-term effects of fine particulate air pollution on cardiovascular hospital emergency room visits: a time-series study in Beijing, China.

PubMed

Su, Chang; Breitner, Susanne; Schneider, Alexandra; Liu, Liqun; Franck, Ulrich; Peters, Annette; Pan, Xiaochuan

2016-05-01

The link between particulate matter (PM) and cardiovascular morbidity has been investigated in numerous studies. Less evidence exists, however, about how age, gender and season may modify this relationship. The aim of this study was to evaluate the association between ambient PM2.5 (PM ≤ 2.5 µm) and daily hospital emergency room visits (ERV) for cardiovascular diseases in Beijing, China. Moreover, potential effect modification by age, gender, season, air mass origin and the specific period with 2008 Beijing Olympic were investigated. Finally, the temporal lag structure of PM2.5 has also been explored. Daily counts of cardiovascular ERV were obtained from the Peking University Third Hospital from January 2007 to December 2008. Concurrently, data on PM2.5, PM10 (PM ≤ 10 µm), nitrogen dioxide and sulfur dioxide concentrations were obtained from monitoring networks and a fixed monitoring station. Poisson regression models adjusting for confounders were used to estimate immediate, delayed and cumulative air pollution effects. The temporal lag structure was also estimated using polynomial distributed lag (PDL) models. We calculated the relative risk (RR) for overall cardiovascular disease ERV as well as for specific causes of disease; and also investigated the potential modifying effect of age, gender, season, air mass origin and the period with 2008 Beijing Olympics. We observed adverse effects of PM2.5 on cardiovascular ERV--an IQR increase (68 μg/m(3)) in PM2.5 was associated with an overall RR of 1.022 (95% CI 0.990-1.057) obtained from PDL model. Strongest effects of PM2.5 on cardiovascular ERV were found for a lag of 7 days; the respective estimate was 1.012 (95% CI 1.002-1.022). The effects were more pronounced in females and in spring. Arrhythmia and cerebrovascular diseases showed a stronger association with PM2.5. We also found stronger PM-effects for stagnant and southern air masses and the period of Olympics modified the air pollution effects. We observed a rather delayed effect of PM2.5 on cardiovascular ERV, which was modified by gender and season. Our findings provide new evidence about effect modifications and may have implications to improve policy making for particulate air pollution standards in Beijing, China.

Associations of Cannabis and Cigarette Use with Depression and Anxiety at Age 18: Findings from the Avon Longitudinal Study of Parents and Children

PubMed Central

Gage, Suzanne H.; Hickman, Matthew; Heron, Jon; Munafò, Marcus R.; Lewis, Glyn; Macleod, John; Zammit, Stanley

2015-01-01

Introduction Substance use is associated with common mental health disorders, but the causal effect of specific substances is uncertain. We investigate whether adolescent cannabis and cigarette use is associated with incident depression and anxiety, while attempting to account for confounding and reverse causation. Methods We used data from ALSPAC, a UK birth cohort study, to investigate associations between cannabis or cigarettes (measured at age 16) and depression or anxiety (measured at age 18), before and after adjustment for pre-birth, childhood and adolescent confounders. Our imputed sample size was 4561 participants. Results Both cannabis (unadjusted OR 1.50, 95% CI 1.26, 1.80) and cigarette use (OR 1.37, 95% CI 1.16, 1.61) increased the odds of developing depression. Adjustment for pre-birth and childhood confounders partly attenuated these relationships though strong evidence of association persisted for cannabis use. There was weak evidence of association for cannabis (fully adjusted OR 1.30, 95% CI 0.98, 1.72) and insufficient evidence for association for cigarette use (fully adjusted OR = 0.97, 95% CI 0.75, 1.24) after mutually adjusting for each other, or for alcohol or other substance use. Neither cannabis nor cigarette use were associated with anxiety after adjustment for pre-birth and childhood confounders. Conclusions Whilst evidence of association between cannabis use and depression persisted after adjusting for pre-term and childhood confounders, our results highlight the difficulties in trying to estimate and interpret independent effects of cannabis and tobacco on psychopathology. Complementary methods are required to robustly examine effects of cannabis and tobacco on psychopathology. PMID:25875443

Estimating the monetary value of willingness to pay for E-book reader's attributes using partially confounded factorial conjoint choice experiment

NASA Astrophysics Data System (ADS)

Yong, Chin-Khian

2013-09-01

A partially confounded factorial conjoint choice experiments design was used to examine the monetary value of the willingness to pay for E-book Reader's attributes. Conjoint analysis is an efficient, cost-effective, and most widely used quantitative method in marketing research to understand consumer preferences and value trade-off. Value can be interpreted by customer or consumer as the received of multiple benefits from a price that was paid. The monetary value of willingness to pay for battery life, internal memory, external memory, screen size, text to Speech, touch screen, and converting handwriting to digital text of E-book reader were estimated in this study. Due to the significant interaction effect of the attributes with the price, the monetary values for the seven attributes were found to be different at different values of odds of purchasing versus not purchasing. The significant interactions effects were one of the main contribution of the partially confounded factorial conjoint choice experiment.

On negative outcome control of unobserved confounding as a generalization of difference-in-differences

PubMed Central

Sofer, Tamar; Richardson, David B.; Colicino, Elena; Schwartz, Joel; Tchetgen Tchetgen, Eric J.

2016-01-01

The difference-in-differences (DID) approach is a well known strategy for estimating the effect of an exposure in the presence of unobserved confounding. The approach is most commonly used when pre-and post-exposure outcome measurements are available, and one can assume that the association of the unobserved confounder with the outcome is equal in the two exposure groups, and constant over time. Then, one recovers the treatment effect by regressing the change in outcome over time on the exposure. In this paper, we interpret the difference-in-differences as a negative outcome control (NOC) approach. We show that the pre-exposure outcome is a negative control outcome, as it cannot be influenced by the subsequent exposure, and it is affected by both observed and unobserved confounders of the exposure-outcome association of interest. The relation between DID and NOC provides simple conditions under which negative control outcomes can be used to detect and correct for confounding bias. However, for general negative control outcomes, the DID-like assumption may be overly restrictive and rarely credible, because it requires that both the outcome of interest and the control outcome are measured on the same scale. Thus, we present a scale-invariant generalization of the DID that may be used in broader NOC contexts. The proposed approach is demonstrated in simulations and on a Normative Aging Study data set, in which Body Mass Index is used for NOC of the relationship between air pollution and inflammatory outcomes. PMID:28239233

Evolutionary theory and teleology.

PubMed

O'Grady, R T

1984-04-21

The order within and among living systems can be explained rationally by postulating a process of descent with modification, effected by factors which are extrinsic or intrinsic to the organisms. Because at the time Darwin proposed his theory of evolution there was no concept of intrinsic factors which could evolve, he postulated a process of extrinsic effects--natural selection. Biological order was thus seen as an imposed, rather than an emergent, property. Evolutionary change was seen as being determined by the functional efficiency (adaptedness) of the organism in its environment, rather than by spontaneous changes in intrinsically generated organizing factors. The initial incompleteness of Darwin's explanatory model, and the axiomatization of its postulates in neo-Darwinism, has resulted in a theory of functionalism, rather than structuralism. As such, it introduces an unnecessary teleology which confounds evolutionary studies and reduces the usefulness of the theory. This problem cannot be detected from within the neo-Darwinian paradigm because the different levels of end-directed activity--teleomatic, teleonomic, and teleological--are not recognized. They are, in fact, considered to influence one another. The theory of nonequilibrium evolution avoids these problems by returning to the basic principles of biological order and developing a structuralist explanation of intrinsically generated change. Extrinsic factors may affect the resultant evolutionary pattern, but they are neither necessary nor sufficient for evolution to occur.

Current approaches used in epidemiologic studies to examine short-term multipollutant air pollution exposures.

PubMed

Davalos, Angel D; Luben, Thomas J; Herring, Amy H; Sacks, Jason D

2017-02-01

Air pollution epidemiology traditionally focuses on the relationship between individual air pollutants and health outcomes (e.g., mortality). To account for potential copollutant confounding, individual pollutant associations are often estimated by adjusting or controlling for other pollutants in the mixture. Recently, the need to characterize the relationship between health outcomes and the larger multipollutant mixture has been emphasized in an attempt to better protect public health and inform more sustainable air quality management decisions. New and innovative statistical methods to examine multipollutant exposures were identified through a broad literature search, with a specific focus on those statistical approaches currently used in epidemiologic studies of short-term exposures to criteria air pollutants (i.e., particulate matter, carbon monoxide, sulfur dioxide, nitrogen dioxide, and ozone). Five broad classes of statistical approaches were identified for examining associations between short-term multipollutant exposures and health outcomes, specifically additive main effects, effect measure modification, unsupervised dimension reduction, supervised dimension reduction, and nonparametric methods. These approaches are characterized including advantages and limitations in different epidemiologic scenarios. By highlighting the characteristics of various studies in which multipollutant statistical methods have been used, this review provides epidemiologists and biostatisticians with a resource to aid in the selection of the most optimal statistical method to use when examining multipollutant exposures. Published by Elsevier Inc.

Confounder summary scores when comparing the effects of multiple drug exposures.

PubMed

Cadarette, Suzanne M; Gagne, Joshua J; Solomon, Daniel H; Katz, Jeffrey N; Stürmer, Til

2010-01-01

Little information is available comparing methods to adjust for confounding when considering multiple drug exposures. We compared three analytic strategies to control for confounding based on measured variables: conventional multivariable, exposure propensity score (EPS), and disease risk score (DRS). Each method was applied to a dataset (2000-2006) recently used to examine the comparative effectiveness of four drugs. The relative effectiveness of risedronate, nasal calcitonin, and raloxifene in preventing non-vertebral fracture, were each compared to alendronate. EPSs were derived both by using multinomial logistic regression (single model EPS) and by three separate logistic regression models (separate model EPS). DRSs were derived and event rates compared using Cox proportional hazard models. DRSs derived among the entire cohort (full cohort DRS) was compared to DRSs derived only among the referent alendronate (unexposed cohort DRS). Less than 8% deviation from the base estimate (conventional multivariable) was observed applying single model EPS, separate model EPS or full cohort DRS. Applying the unexposed cohort DRS when background risk for fracture differed between comparison drug exposure cohorts resulted in -7 to + 13% deviation from our base estimate. With sufficient numbers of exposed and outcomes, either conventional multivariable, EPS or full cohort DRS may be used to adjust for confounding to compare the effects of multiple drug exposures. However, our data also suggest that unexposed cohort DRS may be problematic when background risks differ between referent and exposed groups. Further empirical and simulation studies will help to clarify the generalizability of our findings.

Correlations between cannabis use and IQ change in the Dunedin cohort are consistent with confounding from socioeconomic status

PubMed Central

Rogeberg, Ole

2013-01-01

Does cannabis use have substantial and permanent effects on neuropsychological functioning? Renewed and intense attention to the issue has followed recent research on the Dunedin cohort, which found a positive association between, on the one hand, adolescent-onset cannabis use and dependence and, on the other hand, a decline in IQ from childhood to adulthood [Meier et al. (2012) Proc Natl Acad Sci USA 109(40):E2657–E2664]. The association is given a causal interpretation by the authors, but existing research suggests an alternative confounding model based on time-varying effects of socioeconomic status on IQ. A simulation of the confounding model reproduces the reported associations from the Dunedin cohort, suggesting that the causal effects estimated in Meier et al. are likely to be overestimates, and that the true effect could be zero. Further analyses of the Dunedin cohort are proposed to distinguish between the competing interpretations. Although it would be too strong to say that the results have been discredited, the methodology is flawed and the causal inference drawn from the results premature. PMID:23319626

The “Dry-Run” Analysis: A Method for Evaluating Risk Scores for Confounding Control

PubMed Central

Wyss, Richard; Hansen, Ben B.; Ellis, Alan R.; Gagne, Joshua J.; Desai, Rishi J.; Glynn, Robert J.; Stürmer, Til

2017-01-01

Abstract A propensity score (PS) model's ability to control confounding can be assessed by evaluating covariate balance across exposure groups after PS adjustment. The optimal strategy for evaluating a disease risk score (DRS) model's ability to control confounding is less clear. DRS models cannot be evaluated through balance checks within the full population, and they are usually assessed through prediction diagnostics and goodness-of-fit tests. A proposed alternative is the “dry-run” analysis, which divides the unexposed population into “pseudo-exposed” and “pseudo-unexposed” groups so that differences on observed covariates resemble differences between the actual exposed and unexposed populations. With no exposure effect separating the pseudo-exposed and pseudo-unexposed groups, a DRS model is evaluated by its ability to retrieve an unconfounded null estimate after adjustment in this pseudo-population. We used simulations and an empirical example to compare traditional DRS performance metrics with the dry-run validation. In simulations, the dry run often improved assessment of confounding control, compared with the C statistic and goodness-of-fit tests. In the empirical example, PS and DRS matching gave similar results and showed good performance in terms of covariate balance (PS matching) and controlling confounding in the dry-run analysis (DRS matching). The dry-run analysis may prove useful in evaluating confounding control through DRS models. PMID:28338910

External adjustment sensitivity analysis for unmeasured confounding: an application to coronary stent outcomes, Pennsylvania 2004-2008.

PubMed

Huesch, Marco D

2013-06-01

Assessing the real-world comparative effectiveness of common interventions is challenged by unmeasured confounding. To determine whether the mortality benefit shown for drug-eluting stents (DES) over bare metal stents (BMS) in observational studies persists after controls for/tests for confounding. Retrospective observational study involving 38,019 patients, 65 years or older admitted for an index percutaneous coronary intervention receiving DES or BMS in Pennsylvania in 2004-2005 followed up for death through 3 years. Analysis was at the patient level. Mortality was analyzed with Cox proportional hazards models allowing for stratification by disease severity or DES use propensity, accounting for clustering of patients. Instrumental variables analysis used lagged physician stent usage to proxy for the focal stent type decision. A method originating in work by Cornfield and others in 1954 and popularized by Greenland in 1996 was used to assess robustness to confounding. DES was associated with a significantly lower adjusted risk of death at 3 years in Cox and in instrumented analyses. An implausibly strong hypothetical unobserved confounder would be required to fully explain these results. Confounding by indication can bias observational studies. No strong evidence of such selection biases was found in the reduced risk of death among elderly patients receiving DES instead of BMS in a Pennsylvanian state-wide population. © Health Research and Educational Trust.

Confounding, causality, and confusion: the role of intermediate variables in interpreting observational studies in obstetrics.

PubMed

Ananth, Cande V; Schisterman, Enrique F

2017-08-01

Prospective and retrospective cohorts and case-control studies are some of the most important study designs in epidemiology because, under certain assumptions, they can mimic a randomized trial when done well. These assumptions include, but are not limited to, properly accounting for 2 important sources of bias: confounding and selection bias. While not adjusting the causal association for an intermediate variable will yield an unbiased estimate of the exposure-outcome's total causal effect, it is often that obstetricians will want to adjust for an intermediate variable to assess if the intermediate is the underlying driver of the association. Such a practice must be weighed in light of the underlying research question and whether such an adjustment is necessary should be carefully considered. Gestational age is, by far, the most commonly encountered variable in obstetrics that is often mislabeled as a confounder when, in fact, it may be an intermediate. If, indeed, gestational age is an intermediate but if mistakenly labeled as a confounding variable and consequently adjusted in an analysis, the conclusions can be unexpected. The implications of this overadjustment of an intermediate as though it were a confounder can render an otherwise persuasive study downright meaningless. This commentary provides an exposition of confounding bias, collider stratification, and selection biases, with applications in obstetrics and perinatal epidemiology. Copyright © 2017 Elsevier Inc. All rights reserved.

High temperature effects on out-patient visits and hospital admissions in Chiang Mai, Thailand.

PubMed

Pudpong, Nareerut; Hajat, Shakoor

2011-11-15

This study investigated the short-term effects of temperature on out-patient visits and hospital admissions in Chiang Mai, Thailand. While mortality outcomes in the literature have been reported, there is less evidence of morbidity effects with very few studies conducted in developing countries with subtropical or tropical climate. Time-series regression analysis was employed using generalized negative binomial regression to model the short-term relationships between temperature and morbidity after controlling for seasonal patterns and other potential confounders. Lag effects up to 13 days and effect modification by age (0-14 years, 15-64 years, ≥65 years) were examined. Temperature effects with wide confidence intervals were found, with an increase in diabetic visits of 26.3% (95% CI: 7.1%-49.0%), and circulatory visits of 19.2% (95% CI: 7.0%-32.8%) per 1 °C increase in temperature above an identified threshold of 29 °C. Additionally, there was a rise of both visits (3.7% increase, 95% CI: 1.5%-5.9%) and admissions (5.8% increase, 95% CI: 2.3%-9.3%) due to intestinal infectious disease in association with each 1 °C increase across the whole temperature range. The effects of temperature were stronger in the elderly though not statistically significant. Daily morbidity in Chiang Mai was positively associated with temperature with a lag effect of up to 2 weeks, which was longer than lag effects previously reported. Public health preparedness and interventions should be considered to minimise possible increased hospital visits and admissions during hot weather. Copyright © 2011 Elsevier B.V. All rights reserved.

The role of parenting in the prediction of criminal involvement: findings from a nationally representative sample of youth and a sample of adopted youth.

PubMed

Beaver, Kevin M; Schwartz, Joseph A; Connolly, Eric J; Al-Ghamdi, Mohammed Said; Kobeisy, Ahmed Nezar

2015-03-01

The role of parenting in the development of criminal behavior has been the source of a vast amount of research, with the majority of studies detecting statistically significant associations between dimensions of parenting and measures of criminal involvement. An emerging group of scholars, however, has drawn attention to the methodological limitations-mainly genetic confounding-of the parental socialization literature. The current study addressed this limitation by analyzing a sample of adoptees to assess the association between 8 parenting measures and 4 criminal justice outcome measures. The results revealed very little evidence of parental socialization effects on criminal behavior before controlling for genetic confounding and no evidence of parental socialization effects on criminal involvement after controlling for genetic confounding. (PsycINFO Database Record (c) 2015 APA, all rights reserved).

Syphilis may be a confounding factor, not a causative agent, in syphilitic ALS.

PubMed

Tuk, Bert

2016-01-01

Based upon a review of published clinical observations regarding syphilitic amyotrophic lateral sclerosis (ALS), I hypothesize that syphilis is actually a confounding factor, not a causative factor, in syphilitic ALS. Moreover, I propose that the successful treatment of ALS symptoms in patients with syphilitic ALS using penicillin G and hydrocortisone is an indirect consequence of the treatment regimen and is not due to the treatment of syphilis. Specifically, I propose that the observed effect is due to the various pharmacological activities of penicillin G ( e.g ., a GABA receptor antagonist) and/or the multifaceted pharmacological activity of hydrocortisone. The notion that syphilis may be a confounding factor in syphilitic ALS is highly relevant, as it suggests that treating ALS patients with penicillin G and hydrocortisone-regardless of whether they present with syphilitic ALS or non-syphilitic ALS-may be effective at treating this rapidly progressive, highly devastating disease.

Assessing moderated mediation in linear models requires fewer confounding assumptions than assessing mediation.

PubMed

Loeys, Tom; Talloen, Wouter; Goubert, Liesbet; Moerkerke, Beatrijs; Vansteelandt, Stijn

2016-11-01

It is well known from the mediation analysis literature that the identification of direct and indirect effects relies on strong no unmeasured confounding assumptions of no unmeasured confounding. Even in randomized studies the mediator may still be correlated with unobserved prognostic variables that affect the outcome, in which case the mediator's role in the causal process may not be inferred without bias. In the behavioural and social science literature very little attention has been given so far to the causal assumptions required for moderated mediation analysis. In this paper we focus on the index for moderated mediation, which measures by how much the mediated effect is larger or smaller for varying levels of the moderator. We show that in linear models this index can be estimated without bias in the presence of unmeasured common causes of the moderator, mediator and outcome under certain conditions. Importantly, one can thus use the test for moderated mediation to support evidence for mediation under less stringent confounding conditions. We illustrate our findings with data from a randomized experiment assessing the impact of being primed with social deception upon observer responses to others' pain, and from an observational study of individuals who ended a romantic relationship assessing the effect of attachment anxiety during the relationship on mental distress 2 years after the break-up. © 2016 The British Psychological Society.

Nutritional interventions or exposures in infants and children aged up to 3 years and their effects on subsequent risk of overweight, obesity and body fat: a systematic review of systematic reviews.

PubMed

Patro-Gołąb, Bernadeta; Zalewski, Bartłomiej M; Kołodziej, Maciej; Kouwenhoven, Stefanie; Poston, Lucilla; Godfrey, Keith M; Koletzko, Berthold; van Goudoever, Johannes Bernard; Szajewska, Hania

2016-12-01

This study, performed as part of the international EarlyNutrition research project (http://www.project-earlynutrition.eu), provides a systematic review of systematic reviews on the effects of nutritional interventions or exposures in children (up to 3 years of age) on the subsequent risk of obesity, overweight and adiposity. Electronic databases (including MEDLINE, Embase and Cochrane Library) were searched up until September 2015. Forty systematic reviews were included. A consistent association of breastfeeding with a modest reduction in the risk of later overweight and obesity in childhood and adulthood was found (the odds decreased by 13% based on high-quality studies), but residual confounding cannot be excluded. Lowering the protein content of infant formula is a promising intervention to reduce the risk of later overweight and obesity in children. There is no consistent evidence of an association of the age of introducing complementary foods, sugar-sweetened beverage or energy intake in early childhood with later overweight/obesity, but there are some indications of an association of protein intake during the complementary feeding period with later overweight/obesity. There was inadequate evidence to determine the effects of other nutritional interventions or exposures, including modifications of infant formula composition, fat intake or consumption of different food groups. © 2016 World Obesity Federation.

Volunteering is associated with increased survival in able-bodied participants of the English Longitudinal Study of Ageing

PubMed Central

Rogers, Nina Trivedy; Demakakos, Panayotes; Taylor, Mark Steven; Steptoe, Andrew; Hamer, Mark; Shankar, Aparna

2018-01-01

Background Volunteering has been linked to reduced mortality in older adults but the mechanisms explaining this effect remain unclear. This study investigated whether volunteering is associated with increased survival in participants of the English Longitudinal Study of Ageing and whether differences in survival are modified by functional disabilities. Methods A multivariate Cox Proportional Hazards model was used to estimate the association of volunteering with survival over a period of 10.9 years in 10,324 participants, whilst controlling for selected confounders. To investigate effect modification by disability, the analyses were repeated in participants with and without self-reported functional disabilities. Results Volunteering was associated with a reduced probability of death from all-causes in univariate analyses (HR = 0.65, CI 0.58–0.73, P < 0.0001), but adjustment for covariates rendered this association non-significant (HR = 0.90, CI 0.79–1.01, P = 0.07). Able-bodied volunteers had significantly increased survival compared to able-bodied non-volunteers (HR = 0.81, 95% CI: 0.69 – 0.95, P = 0.009). There was no significant survival advantage among disabled volunteers, compared to disabled non-volunteers (HR = 1.06, CI 0.88–1.29, P = 0.53). Conclusion Volunteering is associated with reduced mortality in older adults in England, but this effect appears to be limited to volunteers who report no disabilities. PMID:26811548

What are the causal effects of breastfeeding on IQ, obesity and blood pressure? Evidence from comparing high-income with middle-income cohorts.

PubMed

Brion, Marie-Jo A; Lawlor, Debbie A; Matijasevich, Alicia; Horta, Bernardo; Anselmi, Luciana; Araújo, Cora L; Menezes, Ana Maria B; Victora, Cesar G; Smith, George Davey

2011-06-01

A novel approach is explored for improving causal inference in observational studies by comparing cohorts from high-income with low- or middle-income countries (LMIC), where confounding structures differ. This is applied to assessing causal effects of breastfeeding on child blood pressure (BP), body mass index (BMI) and intelligence quotient (IQ). Standardized approaches for assessing the confounding structure of breastfeeding by socio-economic position were applied to the British Avon Longitudinal Study of Parents and Children (ALSPAC) (N ≃ 5000) and Brazilian Pelotas 1993 cohorts (N ≃ 1000). This was used to improve causal inference regarding associations of breastfeeding with child BP, BMI and IQ. Analyses were extended to include results from a meta-analysis of five LMICs (N ≃ 10 000) and compared with a randomized trial of breastfeeding promotion. Findings Although higher socio-economic position was strongly associated with breastfeeding in ALSPAC, there was little such patterning in Pelotas. In ALSPAC, breastfeeding was associated with lower BP, lower BMI and higher IQ, adjusted for confounders, but in the directions expected if due to socioeconomic patterning. In contrast, in Pelotas, breastfeeding was not strongly associated with BP or BMI but was associated with higher IQ. Differences in associations observed between ALSPAC and the LMIC meta-analysis were in line with those observed between ALSPAC and Pelotas, but with robust evidence of heterogeneity detected between ALSPAC and the LMIC meta-analysis associations. Trial data supported the conclusions inferred by the cross-cohort comparisons, which provided evidence for causal effects on IQ but not for BP or BMI. While reported associations of breastfeeding with child BP and BMI are likely to reflect residual confounding, breastfeeding may have causal effects on IQ. Comparing associations between populations with differing confounding structures can be used to improve causal inference in observational studies.

Control selection and confounding factors: A lesson from a Japanese case-control study to examine acellular pertussis vaccine effectiveness.

PubMed

Ohfuji, Satoko; Okada, Kenji; Nakano, Takashi; Ito, Hiroaki; Hara, Megumi; Kuroki, Haruo; Hirota, Yoshio

2017-08-24

When using a case-control study design to examine vaccine effectiveness, both the selection of control subjects and the consideration of potential confounders must be the important issues to ensure accurate results. In this report, we described our experience from a case-control study conducted to evaluate the effectiveness of acellular pertussis vaccine combined with diphtheria-tetanus toxoids (DTaP vaccine). Newly diagnosed pertussis cases and age- and sex-matched friend-controls were enrolled, and the history of DTaP vaccination was compared between groups. Logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) of vaccination for development of pertussis. After adjustment for potential confounders, four doses of DTaP vaccination showed a lower OR for pediatrician-diagnosed pertussis (OR=0.11, 95% CI, 0.01-0.99). In addition, the decreasing OR of four doses vaccination was more pronounced for laboratory-confirmed pertussis (OR=0.07, 95%CI, 0.01-0.82). Besides, positive association with pertussis was observed in subjects with a history of steroid treatment (OR=5.67) and those with a recent contact with a lasting cough (OR=4.12). When using a case-control study to evaluate the effectiveness of vaccines, particularly those for uncommon infectious diseases such as pertussis, the use of friend-controls may be optimal due to the fact that they shared a similar experience for exposure to the pathogen as the cases. In addition, to assess vaccine effectiveness as accurately as possible, the effects of confounding should be adequately controlled with a matching or analysis technique. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Mediation analysis with time varying exposures and mediators

PubMed Central

VanderWeele, Tyler J.; Tchetgen Tchetgen, Eric J.

2016-01-01

Summary In this paper we consider causal mediation analysis when exposures and mediators vary over time. We give non-parametric identification results, discuss parametric implementation, and also provide a weighting approach to direct and indirect effects based on combining the results of two marginal structural models. We also discuss how our results give rise to a causal interpretation of the effect estimates produced from longitudinal structural equation models. When there are time-varying confounders affected by prior exposure and mediator, natural direct and indirect effects are not identified. However, we define a randomized interventional analogue of natural direct and indirect effects that are identified in this setting. The formula that identifies these effects we refer to as the “mediational g-formula.” When there is no mediation, the mediational g-formula reduces to Robins’ regular g-formula for longitudinal data. When there are no time-varying confounders affected by prior exposure and mediator values, then the mediational g-formula reduces to a longitudinal version of Pearl’s mediation formula. However, the mediational g-formula itself can accommodate both mediation and time-varying confounders and constitutes a general approach to mediation analysis with time-varying exposures and mediators. PMID:28824285

Mediation analysis with time varying exposures and mediators.

PubMed

VanderWeele, Tyler J; Tchetgen Tchetgen, Eric J

2017-06-01

In this paper we consider causal mediation analysis when exposures and mediators vary over time. We give non-parametric identification results, discuss parametric implementation, and also provide a weighting approach to direct and indirect effects based on combining the results of two marginal structural models. We also discuss how our results give rise to a causal interpretation of the effect estimates produced from longitudinal structural equation models. When there are time-varying confounders affected by prior exposure and mediator, natural direct and indirect effects are not identified. However, we define a randomized interventional analogue of natural direct and indirect effects that are identified in this setting. The formula that identifies these effects we refer to as the "mediational g-formula." When there is no mediation, the mediational g-formula reduces to Robins' regular g-formula for longitudinal data. When there are no time-varying confounders affected by prior exposure and mediator values, then the mediational g-formula reduces to a longitudinal version of Pearl's mediation formula. However, the mediational g-formula itself can accommodate both mediation and time-varying confounders and constitutes a general approach to mediation analysis with time-varying exposures and mediators.

Peritraumatic panic attacks and health outcomes two years after psychological trauma: implications for intervention and research.

PubMed

Boscarino, Joseph A; Adams, Richard E

2009-05-15

Several studies have suggested that experiencing a peritraumatic panic attack (PPA) during a traumatic event predicts future mental health status. Some investigators have suggested that this finding has psychotherapeutic significance. We assessed the hypothesis that PPA was not related to longer-term health status after event exposure, once background confounders were controlled. In our study we assessed exposure to the World Trade Center disaster (WTCD) and other negative life events, demographic factors, social support, self-esteem, and panic attack onset in predicting health outcome among 1681 New York City residents 2 years after the attack. Initial bivariate results indicated that a PPA was related to a number of adverse outcomes 2 years after the WTCD, including posttraumatic stress disorder, depression, poor physical health, anxiety, binge drinking, and mental health treatment seeking. However, when multivariate (MV) models were estimated adjusting for potential confounders, most of these associations were either non-significant or substantially reduced. Contrary to previous predictions, these MV models revealed that recent negative life events and current self-esteem at follow-up were the best predictors of health outcomes, not PPA. Although post-trauma interventions may target individuals who experienced PPA after traumatic exposures, reducing the long-term health consequences following such exposures based on PPA alone may be problematic. Modifications of psychopathology constructs based on the reported correlation between PPA and post-trauma outcomes may be premature.

Childhood Medical and Behavioral Consequences of Maternal Cocaine Use1

PubMed Central

Singer, Lynn; Farkas, Kathleen; Kliegman, Robert

2014-01-01

Reviewed available studies of the impact of fetal cocaine exposure on child medical and developmental outcome, as well as the current status of clinical psychological interventions and research strategies. Current studies are inconclusive but suggest that prenatal exposure to crack-cocaine can have significant effects on the growth and neurological development of the infant, with the potential of later learning and behavioral disabilities. Social-environmental correlates of maternal cocaine use are confounding factors with known negative effects on child outcome. Large, population-based studies using multivariate analyses are needed to determine the independent effects of cocaine on child outcome relative to other confounding variables. PMID:1382125

Diagnostics for Confounding of Time-varying and Other Joint Exposures.

PubMed

Jackson, John W

2016-11-01

The effects of joint exposures (or exposure regimes) include those of adhering to assigned treatment versus placebo in a randomized controlled trial, duration of exposure in a cohort study, interactions between exposures, and direct effects of exposure, among others. Unlike the setting of a single point exposure (e.g., propensity score matching), there are few tools to describe confounding for joint exposures or how well a method resolves it. Investigators need tools that describe confounding in ways that are conceptually grounded and intuitive for those who read, review, and use applied research to guide policy. We revisit the implications of exchangeability conditions that hold in sequentially randomized trials, and the bias structure that motivates the use of g-methods, such as marginal structural models. From these, we develop covariate balance diagnostics for joint exposures that can (1) describe time-varying confounding, (2) assess whether covariates are predicted by prior exposures given their past, the indication for g-methods, and (3) describe residual confounding after inverse probability weighting. For each diagnostic, we present time-specific metrics that encompass a wide class of joint exposures, including regimes of multivariate time-varying exposures in censored data, with multivariate point exposures as a special case. We outline how to estimate these directly or with regression and how to average them over person-time. Using a simulated example, we show how these metrics can be presented graphically. This conceptually grounded framework can potentially aid the transparent design, analysis, and reporting of studies that examine joint exposures. We provide easy-to-use tools to implement it.

The acute effects of outdoor temperature on blood pressure in a panel of elderly hypertensive patients

NASA Astrophysics Data System (ADS)

Chen, Renjie; Lu, Jianxiong; Yu, Qun; Peng, Li; Yang, Dandan; Wang, Cuicui; Kan, Haidong

2015-12-01

Higher level of blood pressure (BP) in winter than in summer has been observed, but the association between temperature and BP and its potential modifiers with adjustment of individual confounders and time trends was rarely explored. We aimed to investigate the association between outdoor temperature and BP and its potential modification factors in a longitudinal panel study in Shanghai, China. From January 2011 to December 2012, we scheduled 54 follow-ups for BP measurements per subject via home visit every other week for 50 elderly hypertensive patients. We applied linear mixed-effect models to analyze the association between temperature and BP after controlling for individual characteristics, antihypertensive medication, comorbidities, and time trends. We evaluated the potential effect modifiers by stratification analyses. For a 1 °C decrease in the average temperature on concurrent day and previous day, systolic BP increased by 0.19 mmHg (95 % confidence interval = 0.06, 0.31) and diastolic BP increased by 0.12 mmHg (95 % confidence interval = 0.03, 0.21). The effect of temperature on BP was stronger among those with older age, female sex, low socioeconomic status, and obese physique. The effect was weak and even null for those taking the angiotensin receptor blockers, angiotensin-converting enzyme inhibitor, or its combination with calcium antagonists. Further, the effect was almost restricted within those having chronic comorbidities. Our results demonstrated that an acute decrease in outdoor temperature was significantly associated with a rise in BP among elderly hypertensive patients, in Shanghai, China. Individual characteristics, antihypertensive medications, and comorbidities may modify this effect.

An analysis of heat effects in different subpopulations of Bangladesh.

PubMed

Burkart, Katrin; Breitner, Susanne; Schneider, Alexandra; Khan, Md Mobarak Hossain; Krämer, Alexander; Endlicher, Wilfried

2014-03-01

A substantial number of epidemiological studies have demonstrated an association between atmospheric conditions and human all-cause as well as cause-specific mortality. However, most research has been performed in industrialised countries, whereas little is known about the atmosphere-mortality relationship in developing countries. Especially with regard to modifications from non-atmospheric conditions and intra-population differences, there is a substantial research deficit. Within the scope of this study, we aimed to investigate the effects of heat in a multi-stratified manner, distinguishing by the cause of death, age, gender, location and socio-economic status. We examined 22,840 death counts using semi-parametric Poisson regression models, adjusting for a multitude of potential confounders. Although Bangladesh is dominated by an increase of mortality with decreasing (equivalent) temperatures over a wide range of values, the findings demonstrated the existence of partly strong heat effects at the upper end of the temperature distribution. Moreover, the study demonstrated that the strength of these heat effects varied considerably over the investigated subgroups. The adverse effects of heat were particularly pronounced for males and the elderly above 65 years. Moreover, we found increased adverse effects of heat for urban areas and for areas with a high socio-economic status. The increase in, and acceleration of, urbanisation in Bangladesh, as well as the rapid aging of the population and the increase in non-communicable diseases, suggest that the relevance of heat-related mortality might increase further. Considering rising global temperatures, the adverse effects of heat might be further aggravated.

Statin adherence and risk of acute cardiovascular events among women: a cohort study accounting for time-dependent confounding affected by previous adherence.

PubMed

Lavikainen, Piia; Helin-Salmivaara, Arja; Eerola, Mervi; Fang, Gang; Hartikainen, Juha; Huupponen, Risto; Korhonen, Maarit Jaana

2016-06-03

Previous studies on the effect of statin adherence on cardiovascular events in the primary prevention of cardiovascular disease have adjusted for time-dependent confounding, but potentially introduced bias into their estimates as adherence and confounders were measured simultaneously. We aimed to evaluate the effect when accounting for time-dependent confounding affected by previous adherence as well as time sequence between factors. Retrospective cohort study. Finnish healthcare registers. Women aged 45-64 years initiating statin use for primary prevention of cardiovascular disease in 2001-2004 (n=42 807). Acute cardiovascular event defined as a composite of acute coronary syndrome and acute ischaemic stroke was our primary outcome. Low-energy fractures were used as a negative control outcome to evaluate the healthy-adherer effect. During the 3-year follow-up, 474 women experienced the primary outcome event and 557 suffered a low-energy fracture. The causal HR estimated with marginal structural model for acute cardiovascular events for all the women who remained adherent (proportion of days covered ≥80%) to statin therapy during the previous adherence assessment year was 0.78 (95% CI: 0.65 to 0.94) when compared with everybody remaining non-adherent (proportion of days covered <80%). The result was robust against alternative model specifications. Statin adherers had a potentially reduced risk of experiencing low-energy fractures compared with non-adherers (HR 0.90, 95% CI 0.76 to 1.07). Our study, which took into account the time dependence of adherence and confounders, as well as temporal order between these factors, is support for the concept that adherence to statins in women in primary prevention decreases the risk of acute cardiovascular events by about one-fifth in comparison to non-adherence. However, part of the observed effect of statin adherence on acute cardiovascular events may be due to the healthy-adherer effect. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Effects of aggregation of drug and diagnostic codes on the performance of the high-dimensional propensity score algorithm: an empirical example.

PubMed

Le, Hoa V; Poole, Charles; Brookhart, M Alan; Schoenbach, Victor J; Beach, Kathleen J; Layton, J Bradley; Stürmer, Til

2013-11-19

The High-Dimensional Propensity Score (hd-PS) algorithm can select and adjust for baseline confounders of treatment-outcome associations in pharmacoepidemiologic studies that use healthcare claims data. How hd-PS performance is affected by aggregating medications or medical diagnoses has not been assessed. We evaluated the effects of aggregating medications or diagnoses on hd-PS performance in an empirical example using resampled cohorts with small sample size, rare outcome incidence, or low exposure prevalence. In a cohort study comparing the risk of upper gastrointestinal complications in celecoxib or traditional NSAIDs (diclofenac, ibuprofen) initiators with rheumatoid arthritis and osteoarthritis, we (1) aggregated medications and International Classification of Diseases-9 (ICD-9) diagnoses into hierarchies of the Anatomical Therapeutic Chemical classification (ATC) and the Clinical Classification Software (CCS), respectively, and (2) sampled the full cohort using techniques validated by simulations to create 9,600 samples to compare 16 aggregation scenarios across 50% and 20% samples with varying outcome incidence and exposure prevalence. We applied hd-PS to estimate relative risks (RR) using 5 dimensions, predefined confounders, ≤ 500 hd-PS covariates, and propensity score deciles. For each scenario, we calculated: (1) the geometric mean RR; (2) the difference between the scenario mean ln(RR) and the ln(RR) from published randomized controlled trials (RCT); and (3) the proportional difference in the degree of estimated confounding between that scenario and the base scenario (no aggregation). Compared with the base scenario, aggregations of medications into ATC level 4 alone or in combination with aggregation of diagnoses into CCS level 1 improved the hd-PS confounding adjustment in most scenarios, reducing residual confounding compared with the RCT findings by up to 19%. Aggregation of codes using hierarchical coding systems may improve the performance of the hd-PS to control for confounders. The balance of advantages and disadvantages of aggregation is likely to vary across research settings.

Coping with confounds in multivoxel pattern analysis: what should we do about reaction time differences? A comment on Todd, Nystrom & Cohen 2013.

PubMed

Woolgar, Alexandra; Golland, Polina; Bode, Stefan

2014-09-01

Multivoxel pattern analysis (MVPA) is a sensitive and increasingly popular method for examining differences between neural activation patterns that cannot be detected using classical mass-univariate analysis. Recently, Todd et al. ("Confounds in multivariate pattern analysis: Theory and rule representation case study", 2013, NeuroImage 77: 157-165) highlighted a potential problem for these methods: high sensitivity to confounds at the level of individual participants due to the use of directionless summary statistics. Unlike traditional mass-univariate analyses where confounding activation differences in opposite directions tend to approximately average out at group level, group level MVPA results may be driven by any activation differences that can be discriminated in individual participants. In Todd et al.'s empirical data, factoring out differences in reaction time (RT) reduced a classifier's ability to distinguish patterns of activation pertaining to two task rules. This raises two significant questions for the field: to what extent have previous multivoxel discriminations in the literature been driven by RT differences, and by what methods should future studies take RT and other confounds into account? We build on the work of Todd et al. and compare two different approaches to remove the effect of RT in MVPA. We show that in our empirical data, in contrast to that of Todd et al., the effect of RT on rule decoding is negligible, and results were not affected by the specific details of RT modelling. We discuss the meaning of and sensitivity for confounds in traditional and multivoxel approaches to fMRI analysis. We observe that the increased sensitivity of MVPA comes at a price of reduced specificity, meaning that these methods in particular call for careful consideration of what differs between our conditions of interest. We conclude that the additional complexity of the experimental design, analysis and interpretation needed for MVPA is still not a reason to favour a less sensitive approach. Copyright © 2014 Elsevier Inc. All rights reserved.

Association between breastfeeding and eczema during childhood and adolescence: A cohort study.

PubMed

Wang, Jingying; Ramette, Alban; Jurca, Maja; Goutaki, Myrofora; Beardsmore, Caroline S; Kuehni, Claudia E

2017-01-01

Breastfeeding is said to protect children from eczema (atopic dermatitis), but the available evidence is conflicting and subject to the influences of parental atopy and reverse causation (when mothers extended duration of breastfeeding because their children had eczema). In the prospective, population-based Leicester Respiratory Cohort study, we assessed duration of breastfeeding in children aged 1-4 years. Prevalence of eczema was determined by questionnaire surveys that were repeated until the children were 17 years old. We investigated the association between having been breastfed and current eczema using generalized estimating equations, adjusting for potential confounders, and tested for effect modification by parental atopy. We also assessed the association between having been breastfed and incident eczema at ages 2, 4, and 6 years using multivariable logistic regression. Among the 5,676 children in the study, 2,284 (40%) had never been breastfed, while 1,610 (28%), 705 (12%), and 1,077 (19%) had been breastfed for 0-3, 4-6, and >6 months, respectively. Prevalence of current eczema decreased from 36% in 1-year-olds to 18% in children aged 10-17 years. Breastfeeding was not associated with current eczema. Compared with children who had never been breastfed, the adjusted odds ratios for current eczema at any age were 1.02 (95% confidence interval 0.90-1.15) for children who had been breastfed for 0-3 months, 0.97 (0.82-1.13) for children breastfed for 4-6 months, and 0.98 (0.85-1.14) for children breastfed for >6 months. There was no strong evidence for an effect modification by parental atopy (p-value for interaction term was 0.061) and no association between having been breastfed and incident eczema later in childhood. This population-based cohort study found no evidence for protection of breastfeeding against childhood eczema at any age, from infancy through adolescence.

Association between breastfeeding and eczema during childhood and adolescence: A cohort study

PubMed Central

Ramette, Alban; Jurca, Maja; Goutaki, Myrofora; Beardsmore, Caroline S.; Kuehni, Claudia E.

2017-01-01

Background Breastfeeding is said to protect children from eczema (atopic dermatitis), but the available evidence is conflicting and subject to the influences of parental atopy and reverse causation (when mothers extended duration of breastfeeding because their children had eczema). Methods In the prospective, population-based Leicester Respiratory Cohort study, we assessed duration of breastfeeding in children aged 1–4 years. Prevalence of eczema was determined by questionnaire surveys that were repeated until the children were 17 years old. We investigated the association between having been breastfed and current eczema using generalized estimating equations, adjusting for potential confounders, and tested for effect modification by parental atopy. We also assessed the association between having been breastfed and incident eczema at ages 2, 4, and 6 years using multivariable logistic regression. Results Among the 5,676 children in the study, 2,284 (40%) had never been breastfed, while 1,610 (28%), 705 (12%), and 1,077 (19%) had been breastfed for 0–3, 4–6, and >6 months, respectively. Prevalence of current eczema decreased from 36% in 1-year-olds to 18% in children aged 10–17 years. Breastfeeding was not associated with current eczema. Compared with children who had never been breastfed, the adjusted odds ratios for current eczema at any age were 1.02 (95% confidence interval 0.90–1.15) for children who had been breastfed for 0–3 months, 0.97 (0.82–1.13) for children breastfed for 4–6 months, and 0.98 (0.85–1.14) for children breastfed for >6 months. There was no strong evidence for an effect modification by parental atopy (p-value for interaction term was 0.061) and no association between having been breastfed and incident eczema later in childhood. Conclusions This population-based cohort study found no evidence for protection of breastfeeding against childhood eczema at any age, from infancy through adolescence. PMID:28945812

Lead-Related Genetic Loci, Cumulative Lead Exposure and Incident Coronary Heart Disease: The Normative Aging Study

PubMed Central

Weisskopf, Marc G.; Sparrow, David; Schwartz, Joel; Hu, Howard; Park, Sung Kyun

2016-01-01

Background Cumulative exposure to lead is associated with cardiovascular outcomes. Polymorphisms in the δ-aminolevulinic acid dehydratase (ALAD), hemochromatosis (HFE), heme oxygenase-1 (HMOX1), vitamin D receptor (VDR), glutathione S-transferase (GST) supergene family (GSTP1, GSTT1, GSTM1), apolipoprotein E (APOE),angiotensin II receptor-1 (AGTR1) and angiotensinogen (AGT) genes, are believed to alter toxicokinetics and/or toxicodynamics of lead. Objectives We assessed possible effect modification by genetic polymorphisms in ALAD, HFE, HMOX1, VDR, GSTP1, GSTT1, GSTM1, APOE, AGTR1 and AGT individually and as the genetic risk score (GRS) on the association between cumulative lead exposure and incident coronary heart disease (CHD) events. Methods We used K-shell-X-ray fluorescence to measure bone lead levels. GRS was calculated on the basis of 22 lead-related loci. We constructed Cox proportional hazard models to compute adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident CHD. We applied inverse probability weighting to account for potential selection bias due to recruitment into the bone lead sub-study. Results Significant effect modification was found by VDR, HMOX1, GSTP1, APOE, and AGT genetic polymorphisms when evaluated individually. Further, the bone lead-CHD associations became larger as GRS increases. After adjusting for potential confounders, a HR of CHD was 2.27 (95%CI: 1.50–3.42) with 2-fold increase in patella lead levels, among participants in the top tertile of GRS. We also detected an increasing trend in HRs across tertiles of GRS (p-trend = 0.0063). Conclusions Our findings suggest that lead-related loci as a whole may play an important role in susceptibility to lead-related CHD risk. These findings need to be validated in a separate cohort containing bone lead, lead-related genetic loci and incident CHD data. PMID:27584680

Medication Use in Early-HD Participants in Track-HD: an Investigation of its Effects on Clinical Performance.

PubMed

Keogh, Ruth; Frost, Chris; Owen, Gail; Daniel, Rhian M; Langbehn, Doug R; Leavitt, Blair; Durr, Alexandra; Roos, Raymund A C; Landwehrmeyer, G Bernhard; Reilmann, Ralf; Borowsky, Beth; Stout, Julie; Craufurd, David; Tabrizi, Sarah J

2016-01-11

 Insufficient evidence exists to guide the long-term pharmacological management of Huntington's disease (HD) although most current interventions rely on symptomatic management. The effect of many frontline treatments on potential endpoints for HD clinical trials remains unknown. Our objective was to investigate how therapies widely used to manage HD affect the symptom for which they are prescribed and other endpoints using data from TRACK-HD. We used longitudinal models to estimate effects of medication use on performance on tests of motor, cognitive and neuropsychiatric function using data from 123 TRACK-HD stage 1/2 participants across four study visits. Adjustment for confounding by prior medication use, prior clinical performance, concomitant use of other medications, and baseline variables (sex, disease group, age, CAG, study site, education) enabled a closer-to-causal interpretation of the associations. Adjusting for baseline variables only, medication use was typically associated with worse clinical performance, reflecting greater medication use in more advanced patients. After additional adjustment for longitudinal confounders such "inverse" associations were generally eliminated and in the expected directions: participants taking neuroleptics tended to have better motor performance, improved affect and poorer cognitive performance, and those taking SSRI/SNRIs had less apathy, less affect and better total behaviour scores. However, we uncovered few statistically significant associations. Limitations include sample size and unmeasured confounding. In conclusion, adjustment for confounding by prior measurements largely eliminated associations between medication use and poorer clinical performance from simple analyses. However, there was little convincing evidence of causal effects of medication on clinical performance and larger cohorts or trials are needed.

Environmental manganese exposure and associations with memory, executive functions, and hyperactivity in Brazilian children.

PubMed

Carvalho, Chrissie Ferreira de; Oulhote, Youssef; Martorelli, Marina; Carvalho, Carla Oliveira de; Menezes-Filho, José Antônio; Argollo, Nayara; Abreu, Neander

2018-02-09

Manganese (Mn) is an essential element, however high levels of Mn have been associated with lower neuropsychological performance and behavioral problems in children. We investigated the associations between hair Mn concentrations and neuropsychological and behavioral performances among children with long-term exposure to airborne Mn aged between 7 and 12 years. Neuropsychological performance included tests of: verbal memory, inhibitory control, cognitive flexibility, verbal fluency, and motor function. We used the Conners Abbreviated Rating Scale for teachers to assess students' behaviors of hyperactivity. Hair manganese (MnH) concentrations in children and exposure to airborne manganese from a ferro-manganese alloy plant were analyzed and correlated with tests scores. Multivariable linear models adjusting for potential confounders showed that elevated levels of MnH were associated with lower performance in verbal memory, as measured by the free recall after interference (β = - 1.8; 95% CI: - 3.4, - 0.2), which indicates susceptibility to interference, and Delayed Effect (β = -2.0; 95% CI: -3.7, - 0.2), representing a loss of information over time. Additionally, we found patterns of effect modification by sex in three subtests measuring verbal memory: the free recall after interference score, Interference Effect, and Delayed Effect (all at p < 0.10). Overall, the results suggest that long-term airborne Mn exposure may be associated with lower performance in verbal memory, and hyperactivity behaviors. Copyright © 2018 Elsevier B.V. All rights reserved.

Discrimination and common mental disorders of undergraduate students of the Universidade Federal de Santa Catarina.

PubMed

de Souza, Maria Vitória Cordeiro; Lemkuhl, Isabel; Bastos, João Luiz

2015-01-01

The pathogenic and consistent effect of discrimination on mental health has been largely documented in the literature. However, there are few studies measuring multiple types of discrimination, evaluating the existence of a dose-response relationship or investigating possible effect modifiers of such an association. To investigate the association between experiences of discrimination attributed to multiple reasons and common mental disorders, including the adjustment for potential confounders, assessment of dose-response relations, and examination of effect modifiers in undergraduate students from southern Brazil. In the first semester of 2012, 1,023 students from the Universidade Federal de Santa Catarina answered a self-administered questionnaire on socio-demographic characteristics, undergraduate course, experiences of discrimination and common mental disorders. Associations were analyzed through logistic regression models, estimation of Odds Ratios and 95% confidence intervals (95%CI). The study results showed that students reporting discrimination at high frequency and intensity were 4.4 (95%CI 1.6 - 12.4) times more likely to present common mental disorders. However, the relationship between discrimination and common mental disorders was protective among Electrical Engineering students, when compared to Accounting Sciences students who did not report discrimination. The findings suggest that the dose-response relationship between experiences of discrimination and common mental disorders reinforces the hypothetical causal nature of this association. Nevertheless, the modification of effect caused by the undergraduate course should be considered in future studies for a better understanding and measurement of both phenomena.

Effects of Age at First Childbirth and Other Factors on Central Obesity in Postmenopausal Women: The 2013–2015 Korean National Health and Nutrition Examination Survey

PubMed Central

Lee, Wang Jin; Lee, Joo Ha; Kwag, Byoung Gyu; Chang, Shin Hae; Choi, Yu Jin

2018-01-01

Background Waist circumference is one of the key components of metabolic syndrome. Recent studies demonstrated that the reproductive profile was associated with metabolic syndrome in postmenopausal women. This study focused on the association between central obesity and age at first childbirth. It also considered other factors associated with central obesity in postmenopausal women. Methods This study was based on the 2013–2015 Korean National Health and Nutrition Examination Survey and involved 3,143 naturally postmenopausal women. These women were divided into three groups according to their age at first childbirth: 19 years or younger (n=252), 20–29 years (n=2,695), and 30 years or older (n=196). Multivariate analysis using logistic regression was performed to evaluate the effects of various reproductive factors, including other confounding factors. Results During adjustment for confounding factors, in the early age at first childbirth group, odds ratios (95% confidence intervals) for central obesity decreased. In the final model, younger age at first childbirth was not significantly related to central obesity (waist circumference more than 85 cm) in naturally postmenopausal women after adjusting for other confounding factors. Conclusion Younger age at first childbirth was not significantly associated with central obesity after adjustment for confounding factors. PMID:29788703

Gene × environment interaction studies have not properly controlled for potential confounders: the problem and the (simple) solution.

PubMed

Keller, Matthew C

2014-01-01

Candidate gene × environment (G × E) interaction research tests the hypothesis that the effects of some environmental variable (e.g., childhood maltreatment) on some outcome measure (e.g., depression) depend on a particular genetic polymorphism. Because this research is inherently nonexperimental, investigators have been rightly concerned that detected interactions could be driven by confounders (e.g., ethnicity, gender, age, socioeconomic status) rather than by the specified genetic or environmental variables per se. In an attempt to eliminate such alternative explanations for detected G × E interactions, investigators routinely enter the potential confounders as covariates in general linear models. However, this practice does not control for the effects these variables might have on the G × E interaction. Rather, to properly control for confounders, researchers need to enter the covariate × environment and the covariate × gene interaction terms in the same model that tests the G × E term. In this manuscript, I demonstrate this point analytically and show that the practice of improperly controlling for covariates is the norm in the G × E interaction literature to date. Thus, many alternative explanations for G × E findings that investigators had thought were eliminated have not been. © 2013 Society of Biological Psychiatry Published by Society of Biological Psychiatry All rights reserved.

Assessing Hospital Performance After Percutaneous Coronary Intervention Using Big Data.

PubMed

Spertus, Jacob V; T Normand, Sharon-Lise; Wolf, Robert; Cioffi, Matt; Lovett, Ann; Rose, Sherri

2016-11-01

Although risk adjustment remains a cornerstone for comparing outcomes across hospitals, optimal strategies continue to evolve in the presence of many confounders. We compared conventional regression-based model to approaches particularly suited to leveraging big data. We assessed hospital all-cause 30-day excess mortality risk among 8952 adults undergoing percutaneous coronary intervention between October 1, 2011, and September 30, 2012, in 24 Massachusetts hospitals using clinical registry data linked with billing data. We compared conventional logistic regression models with augmented inverse probability weighted estimators and targeted maximum likelihood estimators to generate more efficient and unbiased estimates of hospital effects. We also compared a clinically informed and a machine-learning approach to confounder selection, using elastic net penalized regression in the latter case. Hospital excess risk estimates range from -1.4% to 2.0% across methods and confounder sets. Some hospitals were consistently classified as low or as high excess mortality outliers; others changed classification depending on the method and confounder set used. Switching from the clinically selected list of 11 confounders to a full set of 225 confounders increased the estimation uncertainty by an average of 62% across methods as measured by confidence interval length. Agreement among methods ranged from fair, with a κ statistic of 0.39 (SE: 0.16), to perfect, with a κ of 1 (SE: 0.0). Modern causal inference techniques should be more frequently adopted to leverage big data while minimizing bias in hospital performance assessments. © 2016 American Heart Association, Inc.

Breast feeding and resilience against psychosocial stress

PubMed Central

Montgomery, S M; Ehlin, A; Sacker, A

2006-01-01

Background Some early life exposures may result in a well controlled stress response, which can reduce stress related anxiety. Breast feeding may be a marker of some relevant exposures. Aims To assess whether breast feeding is associated with modification of the relation between parental divorce and anxiety. Methods Observational study using longitudinal birth cohort data. Linear regression was used to assess whether breast feeding modifies the association of parental divorce/separation with anxiety using stratification and interaction testing. Data were obtained from the 1970 British Cohort Study, which is following the lives of those born in one week in 1970 and living in Great Britain. This study uses information collected at birth and at ages 5 and 10 years for 8958 subjects. Class teachers answered a question on anxiety among 10 year olds using an analogue scale (range 0–50) that was log transformed to minimise skewness. Results Among 5672 non‐breast fed subjects, parental divorce/separation was associated with a statistically significantly raised risk of anxiety, with a regression coefficient (95% CI) of 9.4 (6.1 to 12.8). Among the breast fed group this association was much lower: 2.2 (−2.6 to 7.0). Interaction testing confirmed statistically significant effect modification by breast feeding, independent of simultaneous adjustment for multiple potential confounding factors, producing an interaction coefficient of −7.0 (−12.8 to −1.2), indicating a 7% reduction in anxiety after adjustment. Conclusions Breast feeding is associated with resilience against the psychosocial stress linked with parental divorce/separation. This could be because breast feeding is a marker of exposures related to maternal characteristics and parent–child interaction. PMID:16887859

Polyclonal antithymocyte globulin and cardiovascular disease in kidney transplant recipients.

PubMed

Ducloux, Didier; Courivaud, Cécile; Bamoulid, Jamal; Crepin, Thomas; Chalopin, Jean-Marc; Tiberghien, Pierre; Saas, Philippe

2014-06-01

T-lymphocyte activation may contribute to atherosclerosis, the prevalence of which is increased in transplant patients. However, the cardiovascular consequences of polyclonal antithymocyte globulin (ATG)-induced immune modifications, which include alterations in T-cell subsets, are unknown. We conducted a retrospective single-center study to assess whether ATG associates with an increased incidence of atherosclerotic events (CVEs) in kidney transplant patients. Propensity score analysis was performed to address potential confounding by indication. We also tested whether ATG use induces a proatherogenic immune status. Sixty-nine (12.2%) CVEs occurred during follow-up (87±31 months). The cumulative incidence of CVEs was higher in ATG-treated patients (14.7% versus 8.2%; P=0.03). Cox regression analysis revealed that ATG use was an independent risk factor for CVEs (hazard ratio [HR], 2.36; 95% confidence interval [95% CI], 1.35 to 4.13; P=0.003). Results obtained in the propensity score match analysis recapitulated those obtained from the overall cohort (HR, 2.09; 95% CI, 1.11 to 3.98; P=0.02). Late-stage differentiated CD8(+) T cells increased 1 year after transplantation only in ATG-treated patients. More generally, ATG associated with features of immune activation. These modifications increased markedly in patients exposed to cytomegalovirus (CMV). Subanalyses suggest that the effect of ATG on CVEs is restricted to CMV-exposed patients. However, CMV infection associated significantly with CVEs only in ATG-treated patients (HR, 2.07; 95% CI, 1.16 to 3.70; P=0.01). In conclusion, ATG associated with both immune activation and post-transplant CVEs in this cohort. Further studies should precisely determine whether ATG-induced immune activation is the causal link between ATG and CVEs. Copyright © 2014 by the American Society of Nephrology.

Polyclonal Antithymocyte Globulin and Cardiovascular Disease in Kidney Transplant Recipients

PubMed Central

Courivaud, Cécile; Bamoulid, Jamal; Crepin, Thomas; Chalopin, Jean-Marc; Tiberghien, Pierre; Saas, Philippe

2014-01-01

T-lymphocyte activation may contribute to atherosclerosis, the prevalence of which is increased in transplant patients. However, the cardiovascular consequences of polyclonal antithymocyte globulin (ATG)–induced immune modifications, which include alterations in T-cell subsets, are unknown. We conducted a retrospective single-center study to assess whether ATG associates with an increased incidence of atherosclerotic events (CVEs) in kidney transplant patients. Propensity score analysis was performed to address potential confounding by indication. We also tested whether ATG use induces a proatherogenic immune status. Sixty-nine (12.2%) CVEs occurred during follow-up (87±31 months). The cumulative incidence of CVEs was higher in ATG-treated patients (14.7% versus 8.2%; P=0.03). Cox regression analysis revealed that ATG use was an independent risk factor for CVEs (hazard ratio [HR], 2.36; 95% confidence interval [95% CI], 1.35 to 4.13; P=0.003). Results obtained in the propensity score match analysis recapitulated those obtained from the overall cohort (HR, 2.09; 95% CI, 1.11 to 3.98; P=0.02). Late-stage differentiated CD8+ T cells increased 1 year after transplantation only in ATG-treated patients. More generally, ATG associated with features of immune activation. These modifications increased markedly in patients exposed to cytomegalovirus (CMV). Subanalyses suggest that the effect of ATG on CVEs is restricted to CMV-exposed patients. However, CMV infection associated significantly with CVEs only in ATG-treated patients (HR, 2.07; 95% CI, 1.16 to 3.70; P=0.01). In conclusion, ATG associated with both immune activation and post-transplant CVEs in this cohort. Further studies should precisely determine whether ATG-induced immune activation is the causal link between ATG and CVEs. PMID:24511120

Amnion as a surrogate tissue reporter of the effects of maternal preeclampsia on the fetus.

PubMed

Suzuki, Masako; Maekawa, Ryo; Patterson, Nicole E; Reynolds, David M; Calder, Brent R; Reznik, Sandra E; Heo, Hye J; Einstein, Francine Hughes; Greally, John M

2016-01-01

Preeclampsia, traditionally characterized by high blood pressure and proteinuria, is a common pregnancy complication, which affects 2-8 % of all pregnancies. Although children born to women with preeclampsia have a higher risk of hypertension in later life, the mechanism of this increased risk is unknown. DNA methylation is an epigenetic modification that has been studied as a mediator of cellular memory of adverse exposures in utero. Since each cell type in the body has a unique DNA profile, cell subtype composition is a major confounding factor in studies of tissues with heterogeneous cell types. The best way to avoid this confounding effect is by using purified cell types. However, using purified cell types in large cohort translational studies is difficult. The amnion, the inner layer of the fetal membranes of the placenta, is derived from the epiblast and consists of two cell types, which are easy to isolate from the delivered placenta. In this study, we demonstrate the value of using amnion samples for DNA methylation studies, revealing distinctive patterns between fetuses exposed to proteinuria or hypertension and fetuses from normal pregnancies. We performed a genome-wide DNA methylation analysis, HpaII tiny fragment Enrichment by Ligation-mediated PCR (HELP)-tagging, on 62 amnion samples from the placentas of uncomplicated, normal pregnancies and from those with complications of preeclampsia or hypertension. Using a regression model approach, we found 123, 85, and 99 loci with high-confidence hypertension-associated, proteinuria-associated, and hypertension- and proteinuria-associated DNA methylation changes, respectively. A gene ontology analysis showed DNA methylation changes to be selecting genes with different biological processes in exposure status. We also found that these differentially methylated regions overlap loci previously reported as differentially methylated regions in preeclampsia. Our findings support prior observations that preeclampsia is associated with changes of DNA methylation near genes that have previously been found to be dysregulated in preeclampsia. We propose that amniotic membranes represent a valuable surrogate fetal tissue on which to perform epigenome-wide association studies of adverse intrauterine conditions.

Hypothyroidism and carpal tunnel syndrome: a meta-analysis.

PubMed

Shiri, Rahman

2014-12-01

This study aimed to assess the magnitude of the association between hypothyroidism and carpal tunnel syndrome (CTS). Eighteen studies were included in a random-effects meta-analysis. A meta-analysis of the studies that did not control their estimates for any confounder showed an association between a thyroid disease (hypo- or hyperthyroidism) and CTS (N = 9,573, effect size [ES] = 1.32 (95% confidence interval [CI], 1.04-1.68) and between hypothyroidism and CTS (N = 64,531, ES = 2.15 [95% CI, 1.64-2.83]). When a meta-analysis limited to the studies that controlled their estimates for some potential confounders, the association between a thyroid disease and CTS disappeared (N = 4,799, ES = 1.17 [95% CI, 0.71-1.92], I(2) = 0%), and the effect size for hypothyroidism largely attenuated (N = 71,133, ES = 1.44 [95% CI, 1.27-1.63], I(2) = 0%). Moreover, there was evidence of publication bias. This meta-analysis found only a modest association between hypothyroidism and CTS. Confounding and publication bias may still account for part of the remaining excess risk. © 2014 Wiley Periodicals, Inc.

Adaptation of metabolism and evaporative water loss along an aridity gradient.

PubMed

Tieleman, B Irene; Williams, Joseph B; Bloomer, Paulette

2003-01-22

Broad-scale comparisons of birds indicate the possibility of adaptive modification of basal metabolic rate (BMR) and total evaporative water loss (TEWL) in species from desert environments, but these might be confounded by phylogeny or phenotypic plasticity. This study relates variation in avian BMR and TEWL to a continuously varying measure of environment, aridity. We test the hypotheses that BMR and TEWL are reduced along an aridity gradient within the lark family (Alaudidae), and investigate the role of phylogenetic inertia. For 12 species of lark, BMR and TEWL decreased along a gradient of increasing aridity, a finding consistent with our proposals. We constructed a phylogeny for 22 species of lark based on sequences of two mitochondrial genes, and investigated whether phylogenetic affinity played a part in the correlation of phenotype and environment. A test for serial independence of the data for mass-corrected TEWL and aridity showed no influence of phylogeny on our findings. However, we did discover a significant phylogenetic effect in mass-corrected data for BMR, a result attributable to common phylogenetic history or to common ecological factors. A test of the relationship between BMR and aridity using phylogenetic independent constrasts was consistent with our previous analysis: BMR decreased with increasing aridity.

Global and local environmental changes as drivers of Buruli ulcer emergence.

PubMed

Combe, Marine; Velvin, Camilla Jensen; Morris, Aaron; Garchitorena, Andres; Carolan, Kevin; Sanhueza, Daniel; Roche, Benjamin; Couppié, Pierre; Guégan, Jean-François; Gozlan, Rodolphe Elie

2017-04-26

Many emerging infectious diseases are caused by generalist pathogens that infect and transmit via multiple host species with multiple dissemination routes, thus confounding the understanding of pathogen transmission pathways from wildlife reservoirs to humans. The emergence of these pathogens in human populations has frequently been associated with global changes, such as socio-economic, climate or biodiversity modifications, by allowing generalist pathogens to invade and persist in new ecological niches, infect new host species, and thus change the nature of transmission pathways. Using the case of Buruli ulcer disease, we review how land-use changes, climatic patterns and biodiversity alterations contribute to disease emergence in many parts of the world. Here we clearly show that Mycobacterium ulcerans is an environmental pathogen characterized by multi-host transmission dynamics and that its infectious pathways to humans rely on the local effects of global environmental changes. We show that the interplay between habitat changes (for example, deforestation and agricultural land-use changes) and climatic patterns (for example, rainfall events), applied in a local context, can lead to abiotic environmental changes and functional changes in local biodiversity that favor the pathogen's prevalence in the environment and may explain disease emergence.

The association between static pelvic asymmetry and low back pain.

PubMed

Levangie, P K

1999-06-15

A cross-sectional case-control approach was used to estimate the association between low back pain of less than 12 months' duration and pelvic asymmetry among 21-50-year-old patients seeking physical therapy services. To evaluate the premise that asymmetrical positioning of the innominates of the pelvis is a source of low back pain. No published studies have been conducted to evaluate systematically the association between low back pain and pelvic asymmetry in a clinic-based sample. Pelvic landmark data were obtained in 144 cases and 138 control subjects. The associations of low back pain with levels of pelvic asymmetry were estimated by use of odds ratios and 95% confidence intervals. Effect modification and confounding of the low back pain-pelvic asymmetry association by several factors was assessed and alternative asymmetry measures considered. Pelvic asymmetry was not positively associated with low back pain in any way that seemed clinically meaningful. Asymmetry of posterior superior iliac spine landmarks showed some evidence of a weak positive association with low back pain. In the absence of meaningful positive association between pelvic asymmetry and low back pain, evaluation and treatment strategies based on this premise should be questioned.

Do non-targeted effects increase or decrease low dose risk in relation to the linear-non-threshold (LNT) model?☆

PubMed Central

Little, M.P.

2011-01-01

In this paper we review the evidence for departure from linearity for malignant and non-malignant disease and in the light of this assess likely mechanisms, and in particular the potential role for non-targeted effects. Excess cancer risks observed in the Japanese atomic bomb survivors and in many medically and occupationally exposed groups exposed at low or moderate doses are generally statistically compatible. For most cancer sites the dose–response in these groups is compatible with linearity over the range observed. The available data on biological mechanisms do not provide general support for the idea of a low dose threshold or hormesis. This large body of evidence does not suggest, indeed is not statistically compatible with, any very large threshold in dose for cancer, or with possible hormetic effects, and there is little evidence of the sorts of non-linearity in response implied by non-DNA-targeted effects. There are also excess risks of various types of non-malignant disease in the Japanese atomic bomb survivors and in other groups. In particular, elevated risks of cardiovascular disease, respiratory disease and digestive disease are observed in the A-bomb data. In contrast with cancer, there is much less consistency in the patterns of risk between the various exposed groups; for example, radiation-associated respiratory and digestive diseases have not been seen in these other (non-A-bomb) groups. Cardiovascular risks have been seen in many exposed populations, particularly in medically exposed groups, but in contrast with cancer there is much less consistency in risk between studies: risks per unit dose in epidemiological studies vary over at least two orders of magnitude, possibly a result of confounding and effect modification by well known (but unobserved) risk factors. In the absence of a convincing mechanistic explanation of epidemiological evidence that is, at present, less than persuasive, a cause-and-effect interpretation of the reported statistical associations for cardiovascular disease is unreliable but cannot be excluded. Inflammatory processes are the most likely mechanism by which radiation could modify the atherosclerotic disease process. If there is to be modification by low doses of ionizing radiation of cardiovascular disease through this mechanism, a role for non-DNA-targeted effects cannot be excluded. PMID:20105434

Combined effect of short-term dehydration and sublethal acute oral dicrotophos exposure confounds the diagnosis of anticholinesterase exposure in common quail (Coturnix coturnix) using plasma cholinesterase activity.

PubMed

Heffernan, James; Mineau, Pierre; Falk, Ramona; Wickstrom, Mark

2012-07-01

Common Quail (Coturnix coturnix) were subjected to controlled and replicated experiments in the summer of 2008 to investigate the effects of short-term dehydration on cholinesterase activity in brain and plasma and the interaction between dehydration and exposure to the organophosphorus pesticide dicrotophos in these same tissues. Our objective was to determine if dehydration could confound the diagnosis of anticholinesterase exposure using inhibition of cholinesterase activity in quail tissues. The effect of dehydration was quantified using measures of plasma osmolality and hematocrit. Dicrotophos exposure caused significant inhibition of cholinesterase activity in brain, while the effects of dehydration and interaction were not significant. Dehydration caused significant duration-dependent increases in plasma osmolality and hematocrit. Dehydration also caused a significant increase in plasma cholinesterase activity. Variation in the change in plasma cholinesterase activity in response to dehydration was significantly and positively correlated with dehydration-induced variation in both the change in plasma osmolality and the change in hematocrit. These correlations suggest that plasma cholinesterase activity in quail is not limited to plasma but occupies some larger pool of the extracellular fluid volume, and we suggest lymph is part of that pool. The effects of dehydration on plasma cholinesterase activity masked the inhibitory effects of dicrotophos. Here, the combination of dehydration and dicrotophos exposure produced plasma cholinesterase activity that was not significantly different from reference and pre-exposure values, confounding the diagnosis of anticholinesterase exposure in dehydrated, dicrotophos-exposed quail. A method to adjust plasma cholinesterase activities for the confounding effects of dehydration and enable the diagnosis of anticholinesterase exposure in dehydrated, dicrotophos-exposed quail was developed. Clinicians and practitioners responsible for the diagnosis of anticholinesterase exposure in birds are cautioned that dehydration, commonly observed in sick wildlife, may mask the effect of anticholinesterases on plasma cholinesterase activity.

Analysis of Longitudinal Studies With Repeated Outcome Measures: Adjusting for Time-Dependent Confounding Using Conventional Methods.

PubMed

Keogh, Ruth H; Daniel, Rhian M; VanderWeele, Tyler J; Vansteelandt, Stijn

2018-05-01

Estimation of causal effects of time-varying exposures using longitudinal data is a common problem in epidemiology. When there are time-varying confounders, which may include past outcomes, affected by prior exposure, standard regression methods can lead to bias. Methods such as inverse probability weighted estimation of marginal structural models have been developed to address this problem. However, in this paper we show how standard regression methods can be used, even in the presence of time-dependent confounding, to estimate the total effect of an exposure on a subsequent outcome by controlling appropriately for prior exposures, outcomes, and time-varying covariates. We refer to the resulting estimation approach as sequential conditional mean models (SCMMs), which can be fitted using generalized estimating equations. We outline this approach and describe how including propensity score adjustment is advantageous. We compare the causal effects being estimated using SCMMs and marginal structural models, and we compare the two approaches using simulations. SCMMs enable more precise inferences, with greater robustness against model misspecification via propensity score adjustment, and easily accommodate continuous exposures and interactions. A new test for direct effects of past exposures on a subsequent outcome is described.

Does the presence of desert dust modify the effect of PM10 on mortality in Athens, Greece?

PubMed

Samoli, Evangelia; Kougea, Evgenia; Kassomenos, Pavlos; Analitis, Antonis; Katsouyanni, Klea

2011-05-01

Recent reports investigate whether windblown desert dust may exacerbate the short-term health effects associated with particulate pollution in urban centers. We have tested this hypothesis by using daily air pollution and mortality data for Athens, Greece during the period 2001-2006. We investigated the effects of exposure to particulate matter with aerodynamic diameter <0μg/m(3) (PM(10)) on total and cause specific mortality, during days with and without windblown desert dust, for all ages, stratified by age groups and by sex. We identified 141 dust days between 2001 and 2006. We used Poisson regression models with penalized splines to control for possible confounding by season, meteorology, day of the week and holiday effect. A 10μg/m(3) increase in PM(10) was associated with a 0.71% (95% confidence interval (CI): 0.42% to 0.99%) increase in all deaths. The effects for total and cause specific mortality were greater for those ≥ 75years of age, while for total mortality higher effects were observed among females. The main effect of desert dust days and its interaction with PM(10) concentrations were significant in all cases except for respiratory mortality and cardiovascular mortality among those < 75years. The negative interaction pointed towards lower particle effects on mortality during dust events. We found evidence of modification of the adverse health effects of PM(10) on mortality in Athens, Greece with desert dust events: the particle effects were significantly higher during non-desert dust days. Our analyses indicate that traffic related particles, which prevail on non-desert dust days, have more toxic effects than the ones originating from long-range transport, such as Sahara dust. Copyright © 2011 Elsevier B.V. All rights reserved.

Have clinical studies demonstrated diabetes prevention or delay of diabetes through early treatment?

PubMed

Southwood, Robin L

2010-01-01

The incidence of type 2 diabetes continues to increase at alarming rates. Prediabetes is a state of abnormal glycemic values that are not abnormal enough to result in the diagnosis of type 2 diabetes. Significant interest in the prevention of diabetes has resulted in trials evaluating pharmacologic intervention and lifestyle intervention to prevent the development of diabetes. Controversy exists over the exact definition of diabetes prevention. Agents might possibly delay diagnosis of diabetes via pharmacologic lowering of blood glucose. Goals of diabetes prevention include decreased cardiovascular disease. Trials assessing diabetes prevention should assess 1) Impact of the study drug upon the incidence of diabetes, 2) Impact of the study drug upon diagnosis of diabetes after post-treatment washout phase, 3) Assessment of insulin sensitivity/@-cell function/insulin secretion and blood glucose, 4) Assessment of confounding factors, 5) Impact of the study drug on the occurrence of cardiovascular disease. The published studies were reviewed using these criteria. Six studies evaluating seven agents have been were reviewed. Six of the seven agents reduced diagnosis of diabetes during use, but only two demonstrated effect after washout phase. One of the two agents has been withdrawn from the market. The second agent had a short follow-up period making the results difficult to interpret. Assessment of insulin secretion at entry to trial was common, however ongoing reassessment was uncommon. All studies attempted to assess confounding factors, however stratification of drug benefit relative to amount of lifestyle modification benefit was not reported in trials. Cardiovascular benefit in the form of reduced hypertension was documented with three agents. Pharmacologic prevention of type 2 diabetes remains unproven, due in part to the difficulty distinguishing between prevention and delay. Reduction in cardiovascular benefit is unproven with most agents studied. Larger studies powered to detect cardiovascular endpoints are necessary to determine benefit of diabetes prevention.

Consumption of Lake Ontario Sport Fish and the Incidence of Colorectal Cancer in the New York State Angler Cohort Study (NYSACS)

PubMed Central

Callahan, Catherine L.; Vena, John E.; Green, Joseph; Swanson, Mya; Mu, Lina; Bonner, Matthew R.

2017-01-01

Fish consumption is hypothesized to reduce the risk of colorectal cancer. Nonetheless, consuming sport fish from the Great Lakes increases exposure to certain persistent organic pollutants, namely polychlorinated biphenyls (PCBs) and organochlorine insecticides, which may increase the risk of cancer. Evidence that exposure to persistent organic pollutants is associated with colorectal cancer is sparse. We examined colorectal cancer incidence in the New York State Angler Cohort Study (NYSACS), a prospective cohort of 17,110 anglers and spouses aged 18 to 40 years at enrollment. In 1991, participants completed a mailed self-administered questionnaire that ascertained the number of years that fish from Lake Ontario were consumed, as well as potential confounders. Forty-one histologically confirmed first primary incident colorectal cancers diagnosed as of December 31, 2008 were identified via the New York State Cancer Registry. Vital status was ascertained by linkage with the Social Security Administration Death File. Rate ratios (RR) and 95% confidence intervals (CI) were calculated with Poisson regression, adjusting for age, pack-years of smoking, and sex. Compared with never consumers, colorectal cancer incidence was statistically non-significantly lower among consumers of Lake Ontario sport fish (RR = 0.66; 95% CI: 0.35; 1.24). Incidence of colon cancer was lower among Lake Ontario fish consumers (RR = 0.45, 95%CI: 0.20; 1.00). We did not observe any evidence of effect measure modification by sex or age. Although consumption of Lake Ontario sport fish may have an inverse association with colorectal cancer risk, inferences are complicated by a small number of cases and a lack of information regarding potential confounders including other dietary factors. However, our results do not provide support for the hypothesis that consumption of contaminated sport fish increases the risk of colorectal cancer. PMID:28040638

Air pollutants and health outcomes: Assessment of confounding by influenza

NASA Astrophysics Data System (ADS)

Thach, Thuan-Quoc; Wong, Chit-Ming; Chan, King-Pan; Chau, Yuen-Kwan; Neil Thomas, G.; Ou, Chun-Quan; Yang, Lin; Peiris, Joseph S. M.; Lam, Tai-Hing; Hedley, Anthony J.

2010-04-01

We assessed confounding of associations between short-term effects of air pollution and health outcomes by influenza using Hong Kong mortality and hospitalization data for 1996-2002. Three measures of influenza were defined: (i) intensity: weekly proportion of positive influenza viruses, (ii) epidemic: weekly number of positive influenza viruses ≥4% of the annual number for ≥2 consecutive weeks, and (iii) predominance: an epidemic period with co-circulation of respiratory syncytial virus <2% of the annual positive isolates for ≥2 consecutive weeks. We examined effects of influenza on associations between nitrogen dioxide (NO 2), sulfur dioxide (SO 2), particulate matter with aerodynamic diameter ≤10 μm (PM 10) and ozone (O 3) and health outcomes including all natural causes mortality, cardiorespiratory mortality and hospitalization. Generalized additive Poisson regression model with natural cubic splines was fitted to control for time-varying covariates to estimate air pollution health effects. Confounding with influenza was assessed using an absolute difference of >0.1% between unadjusted and adjusted excess risks (ER%). Without adjustment, pollutants were associated with positive ER% for all health outcomes except asthma and stroke hospitalization with SO 2 and stroke hospitalization with O 3. Following adjustment, changes in ER% for all pollutants were <0.1% for all natural causes mortality, but >0.1% for mortality from stroke with NO 2 and SO 2, cardiac or heart disease with NO 2, PM 10 and O 3, lower respiratory infections with NO 2 and O 3 and mortality from chronic obstructive pulmonary disease with all pollutants. Changes >0.1% were seen for acute respiratory disease hospitalization with NO 2, SO 2 and O 3 and acute lower respiratory infections hospitalization with PM 10. Generally, influenza does not confound the observed associations of air pollutants with all natural causes mortality and cardiovascular hospitalization, but for some pollutants and subgroups of cardiorespiratory mortality and respiratory hospitalization there was evidence to suggest confounding by influenza.

Considerations for automated machine learning in clinical metabolic profiling: Altered homocysteine plasma concentration associated with metformin exposure.

PubMed

Orlenko, Alena; Moore, Jason H; Orzechowski, Patryk; Olson, Randal S; Cairns, Junmei; Caraballo, Pedro J; Weinshilboum, Richard M; Wang, Liewei; Breitenstein, Matthew K

2018-01-01

With the maturation of metabolomics science and proliferation of biobanks, clinical metabolic profiling is an increasingly opportunistic frontier for advancing translational clinical research. Automated Machine Learning (AutoML) approaches provide exciting opportunity to guide feature selection in agnostic metabolic profiling endeavors, where potentially thousands of independent data points must be evaluated. In previous research, AutoML using high-dimensional data of varying types has been demonstrably robust, outperforming traditional approaches. However, considerations for application in clinical metabolic profiling remain to be evaluated. Particularly, regarding the robustness of AutoML to identify and adjust for common clinical confounders. In this study, we present a focused case study regarding AutoML considerations for using the Tree-Based Optimization Tool (TPOT) in metabolic profiling of exposure to metformin in a biobank cohort. First, we propose a tandem rank-accuracy measure to guide agnostic feature selection and corresponding threshold determination in clinical metabolic profiling endeavors. Second, while AutoML, using default parameters, demonstrated potential to lack sensitivity to low-effect confounding clinical covariates, we demonstrated residual training and adjustment of metabolite features as an easily applicable approach to ensure AutoML adjustment for potential confounding characteristics. Finally, we present increased homocysteine with long-term exposure to metformin as a potentially novel, non-replicated metabolite association suggested by TPOT; an association not identified in parallel clinical metabolic profiling endeavors. While warranting independent replication, our tandem rank-accuracy measure suggests homocysteine to be the metabolite feature with largest effect, and corresponding priority for further translational clinical research. Residual training and adjustment for a potential confounding effect by BMI only slightly modified the suggested association. Increased homocysteine is thought to be associated with vitamin B12 deficiency - evaluation for potential clinical relevance is suggested. While considerations for clinical metabolic profiling are recommended, including adjustment approaches for clinical confounders, AutoML presents an exciting tool to enhance clinical metabolic profiling and advance translational research endeavors.

A flexible, interpretable framework for assessing sensitivity to unmeasured confounding.

PubMed

Dorie, Vincent; Harada, Masataka; Carnegie, Nicole Bohme; Hill, Jennifer

2016-09-10

When estimating causal effects, unmeasured confounding and model misspecification are both potential sources of bias. We propose a method to simultaneously address both issues in the form of a semi-parametric sensitivity analysis. In particular, our approach incorporates Bayesian Additive Regression Trees into a two-parameter sensitivity analysis strategy that assesses sensitivity of posterior distributions of treatment effects to choices of sensitivity parameters. This results in an easily interpretable framework for testing for the impact of an unmeasured confounder that also limits the number of modeling assumptions. We evaluate our approach in a large-scale simulation setting and with high blood pressure data taken from the Third National Health and Nutrition Examination Survey. The model is implemented as open-source software, integrated into the treatSens package for the R statistical programming language. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Theoretical Basis of the Test-Negative Study Design for Assessment of Influenza Vaccine Effectiveness

PubMed Central

Sullivan, Sheena G.; Tchetgen Tchetgen, Eric J.; Cowling, Benjamin J.

2016-01-01

Influenza viruses undergo frequent antigenic changes. As a result, the viruses circulating change within and between seasons, and the composition of the influenza vaccine is updated annually. Thus, estimation of the vaccine's effectiveness is not constant across seasons. In order to provide annual estimates of the influenza vaccine's effectiveness, health departments have increasingly adopted the “test-negative design,” using enhanced data from routine surveillance systems. In this design, patients presenting to participating general practitioners with influenza-like illness are swabbed for laboratory testing; those testing positive for influenza virus are defined as cases, and those testing negative form the comparison group. Data on patients' vaccination histories and confounder profiles are also collected. Vaccine effectiveness is estimated from the odds ratio comparing the odds of testing positive for influenza among vaccinated patients and unvaccinated patients, adjusting for confounders. The test-negative design is purported to reduce bias associated with confounding by health-care-seeking behavior and misclassification of cases. In this paper, we use directed acyclic graphs to characterize potential biases in studies of influenza vaccine effectiveness using the test-negative design. We show how studies using this design can avoid or minimize bias and where bias may be introduced with particular study design variations. PMID:27587721

Bias with respect to socioeconomic status: A closer look at zip code matching in a pneumococcal vaccine effectiveness study.

PubMed

Link-Gelles, Ruth; Westreich, Daniel; Aiello, Allison E; Shang, Nong; Weber, David J; Holtzman, Corinne; Scherzinger, Karen; Reingold, Arthur; Schaffner, William; Harrison, Lee H; Rosen, Jennifer B; Petit, Susan; Farley, Monica; Thomas, Ann; Eason, Jeffrey; Wigen, Christine; Barnes, Meghan; Thomas, Ola; Zansky, Shelley; Beall, Bernard; Whitney, Cynthia G; Moore, Matthew R

2016-12-01

In 2010, 13-valent pneumococcal conjugate vaccine (PCV13) was introduced in the US for prevention of invasive pneumococcal disease in children. Individual-level socioeconomic status (SES) is a potential confounder of the estimated effectiveness of PCV13 and is often controlled for in observational studies using zip code as a proxy. We assessed the utility of zip code matching for control of SES in a post-licensure evaluation of the effectiveness of PCV13 (calculated as [1-matched odds ratio]*100). We used a directed acyclic graph to identify subsets of confounders and collected SES variables from birth certificates, geo-coding, a parent interview, and follow-up with medical providers. Cases tended to be more affluent than eligible controls (for example, 48.3% of cases had private insurance vs. 44.6% of eligible controls), but less affluent than enrolled controls (52.9% of whom had private insurance). Control of confounding subsets, however, did not result in a meaningful change in estimated vaccine effectiveness (original estimate: 85.1%, 95% CI 74.8-91.9%; adjusted estimate: 82.5%, 95% CI 65.6-91.1%). In the context of a post-licensure vaccine effectiveness study, zip code appears to be an adequate, though not perfect, proxy for individual SES.

Using instrumental variables to disentangle treatment and placebo effects in blinded and unblinded randomized clinical trials influenced by unmeasured confounders

NASA Astrophysics Data System (ADS)

Chaibub Neto, Elias

2016-11-01

Clinical trials traditionally employ blinding as a design mechanism to reduce the influence of placebo effects. In practice, however, it can be difficult or impossible to blind study participants and unblinded trials are common in medical research. Here we show how instrumental variables can be used to quantify and disentangle treatment and placebo effects in randomized clinical trials comparing control and active treatments in the presence of confounders. The key idea is to use randomization to separately manipulate treatment assignment and psychological encouragement conversations/interactions that increase the participants’ desire for improved symptoms. The proposed approach is able to improve the estimation of treatment effects in blinded studies and, most importantly, opens the doors to account for placebo effects in unblinded trials.

Identifying cis-mediators for trans-eQTLs across many human tissues using genomic mediation analysis

PubMed Central

Yang, Fan; Wang, Jiebiao; Pierce, Brandon L.; Chen, Lin S.

2017-01-01

The impact of inherited genetic variation on gene expression in humans is well-established. The majority of known expression quantitative trait loci (eQTLs) impact expression of local genes (cis-eQTLs). More research is needed to identify effects of genetic variation on distant genes (trans-eQTLs) and understand their biological mechanisms. One common trans-eQTLs mechanism is “mediation” by a local (cis) transcript. Thus, mediation analysis can be applied to genome-wide SNP and expression data in order to identify transcripts that are “cis-mediators” of trans-eQTLs, including those “cis-hubs” involved in regulation of many trans-genes. Identifying such mediators helps us understand regulatory networks and suggests biological mechanisms underlying trans-eQTLs, both of which are relevant for understanding susceptibility to complex diseases. The multitissue expression data from the Genotype-Tissue Expression (GTEx) program provides a unique opportunity to study cis-mediation across human tissue types. However, the presence of complex hidden confounding effects in biological systems can make mediation analyses challenging and prone to confounding bias, particularly when conducted among diverse samples. To address this problem, we propose a new method: Genomic Mediation analysis with Adaptive Confounding adjustment (GMAC). It enables the search of a very large pool of variables, and adaptively selects potential confounding variables for each mediation test. Analyses of simulated data and GTEx data demonstrate that the adaptive selection of confounders by GMAC improves the power and precision of mediation analysis. Application of GMAC to GTEx data provides new insights into the observed patterns of cis-hubs and trans-eQTL regulation across tissue types. PMID:29021290

Identifying cis-mediators for trans-eQTLs across many human tissues using genomic mediation analysis.

PubMed

Yang, Fan; Wang, Jiebiao; Pierce, Brandon L; Chen, Lin S

2017-11-01

The impact of inherited genetic variation on gene expression in humans is well-established. The majority of known expression quantitative trait loci (eQTLs) impact expression of local genes ( cis -eQTLs). More research is needed to identify effects of genetic variation on distant genes ( trans -eQTLs) and understand their biological mechanisms. One common trans -eQTLs mechanism is "mediation" by a local ( cis ) transcript. Thus, mediation analysis can be applied to genome-wide SNP and expression data in order to identify transcripts that are " cis -mediators" of trans -eQTLs, including those " cis -hubs" involved in regulation of many trans -genes. Identifying such mediators helps us understand regulatory networks and suggests biological mechanisms underlying trans -eQTLs, both of which are relevant for understanding susceptibility to complex diseases. The multitissue expression data from the Genotype-Tissue Expression (GTEx) program provides a unique opportunity to study cis -mediation across human tissue types. However, the presence of complex hidden confounding effects in biological systems can make mediation analyses challenging and prone to confounding bias, particularly when conducted among diverse samples. To address this problem, we propose a new method: Genomic Mediation analysis with Adaptive Confounding adjustment (GMAC). It enables the search of a very large pool of variables, and adaptively selects potential confounding variables for each mediation test. Analyses of simulated data and GTEx data demonstrate that the adaptive selection of confounders by GMAC improves the power and precision of mediation analysis. Application of GMAC to GTEx data provides new insights into the observed patterns of cis -hubs and trans -eQTL regulation across tissue types. © 2017 Yang et al.; Published by Cold Spring Harbor Laboratory Press.

A sequential Cox approach for estimating the causal effect of treatment in the presence of time-dependent confounding applied to data from the Swiss HIV Cohort Study.

PubMed

Gran, Jon Michael; Røysland, Kjetil; Wolbers, Marcel; Didelez, Vanessa; Sterne, Jonathan A C; Ledergerber, Bruno; Furrer, Hansjakob; von Wyl, Viktor; Aalen, Odd O

2010-11-20

When estimating the effect of treatment on HIV using data from observational studies, standard methods may produce biased estimates due to the presence of time-dependent confounders. Such confounding can be present when a covariate, affected by past exposure, is both a predictor of the future exposure and the outcome. One example is the CD4 cell count, being a marker for disease progression for HIV patients, but also a marker for treatment initiation and influenced by treatment. Fitting a marginal structural model (MSM) using inverse probability weights is one way to give appropriate adjustment for this type of confounding. In this paper we study a simple and intuitive approach to estimate similar treatment effects, using observational data to mimic several randomized controlled trials. Each 'trial' is constructed based on individuals starting treatment in a certain time interval. An overall effect estimate for all such trials is found using composite likelihood inference. The method offers an alternative to the use of inverse probability of treatment weights, which is unstable in certain situations. The estimated parameter is not identical to the one of an MSM, it is conditioned on covariate values at the start of each mimicked trial. This allows the study of questions that are not that easily addressed fitting an MSM. The analysis can be performed as a stratified weighted Cox analysis on the joint data set of all the constructed trials, where each trial is one stratum. The model is applied to data from the Swiss HIV cohort study. Copyright © 2010 John Wiley & Sons, Ltd.

The Effect of Clinical Care Location on Clinical Outcomes After Peripheral Vascular Intervention in Medicare Beneficiaries.

PubMed

Turley, Ryan S; Mi, Xiaojuan; Qualls, Laura G; Vemulapalli, Sreekanth; Peterson, Eric D; Patel, Manesh R; Curtis, Lesley H; Jones, W Schuyler

2017-06-12

Modifications in reimbursement rates by Medicare in 2008 have led to peripheral vascular interventions (PVI) being performed more commonly in outpatient and office-based clinics. The objective of this study was to determine the effects of this shift in clinical care setting on clinical outcomes after PVI. Modifications in reimbursement have led to peripheral vascular intervention (PVI) being more commonly performed in outpatient hospital settings and office-based clinics. Using a 100% national sample of Medicare beneficiaries from 2010 to 2012, we examined 30-day and 1-year rates of all-cause mortality, major lower extremity amputation, repeat revascularization, and all-cause hospitalization by clinical care location of index PVI. A total of 218,858 Medicare beneficiaries underwent an index PVI between 2010 and 2012. Index PVIs performed in inpatient settings were associated with higher 1-year rates of all-cause mortality (23.6% vs. 10.4% and 11.7%; p < 0.001), major lower extremity amputation (10.1% vs. 3.7% and 3.5%; p < 0.001), and all-cause repeat hospitalization (63.3% vs. 48.5% and 48.0%; p < 0.001), but lower rates of repeat revascularization (25.1% vs. 26.9% vs. 38.6%; p < 0.001) when compared with outpatient hospital settings and office-based clinics, respectively. After adjustment for potential confounders, patients treated in office-based clinics remained more likely than patients in inpatient hospital settings to require repeat revascularization within 1 year across all specialties. There was also a statistically significant interaction effect between location of index revascularization and geographic region on the occurrence of all-cause hospitalization, repeat revascularization, and lower extremity amputation. Index PVI performed in office-based settings was associated with a higher hazard of repeat revascularization when compared with other settings. Differences in clinical outcomes across treatment settings and geographic regions suggest that inconsistent application of PVI may exist and highlights the need for studies to determine optimal delivery of PVI in clinical practice. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Kidney Function and Cardiovascular Events in Postmenopausal Women: The Impact of Race and Ethnicity in the Women’s Health Initiative

PubMed Central

Arce, Cristina M.; Rhee, Jinnie J.; Cheung, Katharine L.; Hedlin, Haley; Kapphahn, Kristopher; Franceschini, Nora; Kalil, Roberto S.; Martin, Lisa W.; Qi, Lihong; Shara, Nawar M.; Desai, Manisha; Stefanick, Marcia L.; Winkelmayer, Wolfgang C.

2015-01-01

Background Kidney disease disproportionately affects minority populations including African Americans and Hispanics; therefore, understanding the relationship of kidney function to cardiovascular (CV) outcomes within different racial/ethnic groups is of considerable interest. We investigated the relationship between kidney function and CV events and assessed effect modification by race/ethnicity in the Women’s Health Initiative. Study Design Prospective cohort study Setting & Participants Baseline serum creatinine concentrations (assay traceable to isotope-dilution mass spectrometry standard) of 19,411 postmenopausal women aged 50–79 years who self-identified as either non-Hispanic white (n=8921), African American (n=7436), or Hispanic (n=3054) were used to calculate estimated glomerular filtration rates (eGFRs). Predictors Categories of eGFR (exposure); race/ethnicity (effect modifier). Outcomes The primary outcome was the composite of three physician-adjudicated CV events: myocardial infarction (MI), stroke, or CV-related death. Measurements We evaluated the multivariable-adjusted associations between categories of eGFR and CV events using proportional hazards regression and formally tested for effect modification by race/ethnicity. Results Over a mean follow-up of 7.6 years, 1424 CV events (653 MI, 627 strokes, 297 CV-related deaths) were observed. The association between eGFR and CV events was curvilinear; however, the association of eGFR with CV outcomes differed by race (P=0.006). In stratified analyses, we observed that the U-shaped association was present in non-Hispanic whites, whereas African American participants had a rather curvilinear relationship with lower eGFR being associated with higher CV risk and higher eGFR with reduced CV risk. Analyses among Hispanic women were inconclusive owing to few Hispanic women having very low or high eGFR and very few events occurring in these categories. Limitations Lack of urinary albumin measurements; residual confounding by unmeasured or imprecisely measured characteristics. Conclusions In postmenopausal women, the patterns of association between eGFR and CV risk differed between non-Hispanic whites and African American women. PMID:26337132

Understanding Confounding Effects in Linguistic Coordination: An Information-Theoretic Approach

PubMed Central

Gao, Shuyang; Ver Steeg, Greg; Galstyan, Aram

2015-01-01

We suggest an information-theoretic approach for measuring stylistic coordination in dialogues. The proposed measure has a simple predictive interpretation and can account for various confounding factors through proper conditioning. We revisit some of the previous studies that reported strong signatures of stylistic accommodation, and find that a significant part of the observed coordination can be attributed to a simple confounding effect—length coordination. Specifically, longer utterances tend to be followed by longer responses, which gives rise to spurious correlations in the other stylistic features. We propose a test to distinguish correlations in length due to contextual factors (topic of conversation, user verbosity, etc.) and turn-by-turn coordination. We also suggest a test to identify whether stylistic coordination persists even after accounting for length coordination and contextual factors. PMID:26115446

Gang membership and substance use: guilt as a gendered causal pathway

PubMed Central

Coffman, Donna L.; Melde, Chris; Esbensen, Finn-Aage

2014-01-01

Objectives We examine whether anticipated guilt for substance use is a gendered mechanism underlying the noted enhancement effect of gang membership on illegal drug use. We also demonstrate a method for making stronger causal inferences when assessing mediation in the presence of moderation and time-varying confounding. Methods We estimate a series of inverse propensity weighted models to obtain unbiased estimates of mediation in the presence of confounding of the exposure (i.e., gang membership) and mediator (i.e., anticipated guilt) using three waves of data from a multi-site panel study of a law-related education program for youth (N=1,113). Results The onset of gang membership significantly decreased anticipated substance use guilt among both male and female respondents. This reduction was significantly associated with increased frequency of substance use only for female respondents, however, suggesting that gender moderates the mechanism through which gang membership influences substance use. Conclusions Criminologists are often concerned with identifying causal pathways for antisocial and/or delinquent behavior, but confounders of the exposure, mediator, and outcome often interfere with efforts to assess mediation. Many new approaches have been proposed for strengthening causal inference for mediation effects. After controlling for confounding using inverse propensity weighting, our results suggest that interventions aimed at reducing substance use by current and former female gang members should focus on the normative aspects of these behaviors. PMID:26190954

Gang membership and substance use: guilt as a gendered causal pathway.

PubMed

Coffman, Donna L; Melde, Chris; Esbensen, Finn-Aage

2015-03-01

We examine whether anticipated guilt for substance use is a gendered mechanism underlying the noted enhancement effect of gang membership on illegal drug use. We also demonstrate a method for making stronger causal inferences when assessing mediation in the presence of moderation and time-varying confounding. We estimate a series of inverse propensity weighted models to obtain unbiased estimates of mediation in the presence of confounding of the exposure (i.e., gang membership) and mediator (i.e., anticipated guilt) using three waves of data from a multi-site panel study of a law-related education program for youth ( N =1,113). The onset of gang membership significantly decreased anticipated substance use guilt among both male and female respondents. This reduction was significantly associated with increased frequency of substance use only for female respondents, however, suggesting that gender moderates the mechanism through which gang membership influences substance use. Criminologists are often concerned with identifying causal pathways for antisocial and/or delinquent behavior, but confounders of the exposure, mediator, and outcome often interfere with efforts to assess mediation. Many new approaches have been proposed for strengthening causal inference for mediation effects. After controlling for confounding using inverse propensity weighting, our results suggest that interventions aimed at reducing substance use by current and former female gang members should focus on the normative aspects of these behaviors.

Physical activity and risk of type 2 diabetes among Native Hawaiians, Japanese Americans, and Caucasians: the Multiethnic Cohort.

PubMed

Steinbrecher, Astrid; Erber, Eva; Grandinetti, Andrew; Nigg, Claudio; Kolonel, Laurence N; Maskarinec, Gertraud

2012-07-01

Physical inactivity is an established risk factor for diabetes; however, little is known about this association across ethnic groups with different diabetes risk. Therefore, we evaluated the association between physical activity and diabetes and potential effect modification by ethnicity in the Hawaii component of the Multiethnic Cohort. Participants, aged 45 to 75 years, were enrolled by completing a questionnaire on demographics, diet, and self-reported weekly hours of strenuous sports, vigorous work, and moderate activity. Among the 74,913 participants (39% Caucasian, 14% Native Hawaiian, 47% Japanese American), 8561 incident diabetes cases were identified by self-report, a medication questionnaire, and through health plan linkages. Cox regression was applied to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) while adjusting for known confounders. Engaging in strenuous sports was inversely related to diabetes risk with HRs (4+ hours/week vs. never) of 0.67 (95%CI: 0.57-0.79) in women and 0.80 (95%CI: 0.72-0.88) in men. In stratified analyses, the inverse association was consistent across ethnic groups. The inverse association of vigorous work with diabetes was limited to men, while beneficial effects of moderate activity were observed only in Caucasians. These findings support a role of high-intensity physical activity and ethnic-specific guidelines in diabetes prevention.

Traffic-related air pollution and sleep in the Boston Area Community Health Survey.

PubMed

Fang, Shona C; Schwartz, Joel; Yang, May; Yaggi, H Klar; Bliwise, Donald L; Araujo, Andre B

2015-01-01

Little is known about environmental determinants of sleep. We investigated the association between black carbon (BC), a marker of traffic-related air pollution, and sleep measures among participants of the Boston Area Community Health Survey. We also sought to assess the impact of sociodemographic factors, health conditions, and season on associations. Residential 24-h BC was estimated from a validated land-use regression model for 3821 participants and averaged over 1-6 months and 1 year. Sleep measures included questionnaire-assessed sleep duration, sleep latency, and sleep apnea. Linear and logistic regression models controlling for confounders estimated the association between sleep measures and BC. Effect modification was tested with interaction terms. Main effects were not observed between BC and sleep measures. However, in stratified models, males experienced 0.23 h less sleep (95% CI: -0.42, -0.03) and those with low SES 0.25 h less sleep (95% CI: -0.48, -0.01) per IQR increase in annual BC (0.21 μg/m(3)). In blacks, sleep duration increased with annual BC (β=0.34 per IQR; 95% CI: 0.12, 0.57). Similar findings were observed for short sleep (≤5 h). BC was not associated with sleep apnea or sleep latency, however, long-term exposure may be associated with shorter sleep duration, particularly in men and those with low SES, and longer sleep duration in blacks.

Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5·24 million UK adults.

PubMed

Bhaskaran, Krishnan; Douglas, Ian; Forbes, Harriet; dos-Santos-Silva, Isabel; Leon, David A; Smeeth, Liam

2014-08-30

High body-mass index (BMI) predisposes to several site-specific cancers, but a large-scale systematic and detailed characterisation of patterns of risk across all common cancers adjusted for potential confounders has not previously been undertaken. We aimed to investigate the links between BMI and the most common site-specific cancers. With primary care data from individuals in the Clinical Practice Research Datalink with BMI data, we fitted Cox models to investigate associations between BMI and 22 of the most common cancers, adjusting for potential confounders. We fitted linear then non-linear (spline) models; investigated effect modification by sex, menopausal status, smoking, and age; and calculated population effects. 5·24 million individuals were included; 166,955 developed cancers of interest. BMI was associated with 17 of 22 cancers, but effects varied substantially by site. Each 5 kg/m(2) increase in BMI was roughly linearly associated with cancers of the uterus (hazard ratio [HR] 1·62, 99% CI 1·56-1·69; p<0·0001), gallbladder (1·31, 1·12-1·52; p<0·0001), kidney (1·25, 1·17-1·33; p<0·0001), cervix (1·10, 1·03-1·17; p=0·00035), thyroid (1·09, 1·00-1·19; p=0·0088), and leukaemia (1·09, 1·05-1·13; p≤0·0001). BMI was positively associated with liver (1·19, 1·12-1·27), colon (1·10, 1·07-1·13), ovarian (1·09, 1.04-1.14), and postmenopausal breast cancers (1·05, 1·03-1·07) overall (all p<0·0001), but these effects varied by underlying BMI or individual-level characteristics. We estimated inverse associations with prostate and premenopausal breast cancer risk, both overall (prostate 0·98, 0·95-1·00; premenopausal breast cancer 0·89, 0·86-0·92) and in never-smokers (prostate 0·96, 0·93-0·99; premenopausal breast cancer 0·89, 0·85-0·94). By contrast, for lung and oral cavity cancer, we observed no association in never smokers (lung 0·99, 0·93-1·05; oral cavity 1·07, 0·91-1·26): inverse associations overall were driven by current smokers and ex-smokers, probably because of residual confounding by smoking amount. Assuming causality, 41% of uterine and 10% or more of gallbladder, kidney, liver, and colon cancers could be attributable to excess weight. We estimated that a 1 kg/m(2) population-wide increase in BMI would result in 3790 additional annual UK patients developing one of the ten cancers positively associated with BMI. BMI is associated with cancer risk, with substantial population-level effects. The heterogeneity in the effects suggests that different mechanisms are associated with different cancer sites and different patient subgroups. National Institute for Health Research, Wellcome Trust, and Medical Research Council. Copyright © 2014 Bhaskaran et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved.

Estimating influenza vaccine effectiveness: Evolution of methods to better understand effects of confounding in older adults.

PubMed

McElhaney, Janet E; Andrew, Melissa K; McNeil, Shelly A

2017-11-01

Older adults are at high risk for serious complications of influenza illness and loss of vaccine-mediated protection. It is increasingly recognized that in addition to age, multiple chronic conditions and associated frailty contribute to the decline in vaccine effectiveness in this population. However, observational studies have been fraught with issues of confounding related to the degree of frailty and functional decline, measures of which are not included in standard administrative health care databases that are used to calculate vaccine effectiveness. This issue has led to the identification of confounding by indication or from "healthy vaccinee" bias, which respectively lead to underestimates or overestimates of influenza vaccine effectiveness. In addition, the sensitivity and specificity of the criteria used to define influenza-like illness declines with increasing age due to atypical presentations of illness and the inability to distinguish between influenza and other respiratory viruses. The test-negative case:control design has emerged as a method to estimate influenza vaccine effectiveness by comparing vaccination rates in those with laboratory-confirmed influenza to those with other acute viral respiratory illnesses. This review provides a perspective on how test-negative case:control study designs and new insights into mechanisms of protection have considerably strengthened influenza vaccination policy decisions for older adults that have historically been undermined by the conclusions of observational studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Review of Non-Cancer Effects, Especially Circulatory and Ocular Diseases1

PubMed Central

Little, Mark P.

2014-01-01

There is a well-established association between high doses (> 5 Gy) of ionizing radiation exposure and damage to the heart and coronary arteries, although only recently have studies with high quality individual dosimetry been conducted that would enable quantification of this risk adjusting for concomitant chemotherapy. The association between lower dose exposures and late occurring circulatory disease has only recently begun to emerge in the Japanese atomic bomb survivors and in various occupationally-exposed cohorts, and is still controversial. Excess relative risks per unit dose in moderate and low dose epidemiological studies are somewhat variable, possibly a result of confounding and effect modification by well known (but unobserved) risk factors. Radiation doses of 1 Gy or more are associated with increased risk of posterior subcapsular cataract. Accumulating evidence from the Japanese atomic bomb survivors, Chernobyl liquidators, US astronauts and various other exposed groups suggest that cortical cataracts may also be associated with ionizing radiation, although there is little evidence that nuclear cataracts are radiogenic. The dose response appears to be linear, although modest thresholds (of no more than about 0.6 Gy) cannot be ruled out. A variety of other non-malignant effects have been observed after moderate/low dose exposure in various groups, in particular respiratory and digestive disease and central nervous system (and in particular neuro-cognitive) damage. However, because these are generally only observed in isolated groups, or because the evidence is excessively heterogeneous, these associations must be treated with caution. PMID:23903347

Does the Alcohol Make Them Do It? Dating Violence Perpetration and Drinking Among Youth

PubMed Central

Rothman, Emily F.; McNaughton Reyes, Luz; Johnson, Renee M.; LaValley, Michael

2012-01-01

Strong evidence links alcohol use to partner violence perpetration among adults, but the relation between youth alcohol use and dating violence perpetration (DVP) is not as well studied. The authors used meta-analytic procedures to evaluate current knowledge on the association between alcohol use and DVP among youth. The authors reviewed 28 studies published in 1985–2010; most (82%) were cross-sectional. Alcohol use was measured in 3 main ways: 1) frequency or quantity of use, 2) frequency of heavy episodic drinking, or 3) problem use. Collectively, results support the conclusion that higher levels of alcohol use are positively associated with youth DVP. With fixed-effects models, the combined odds ratios for DVP for frequency/quantity, heavy episodic drinking, and problem use were 1.23 (95% confidence interval (CI): 1.16, 1.31), 1.47 (95% CI: 1.17, 1.85), and 2.33 (95% CI: 1.94, 2.80), respectively. This association persisted even after accounting for heterogeneity and publication bias. No studies were designed to assess the immediate temporal association between drinking and DVP. Future research should assess whether there are acute or pharmacologic effects of alcohol use on youth DVP. Furthermore, few studies have been hypothesis driven, controlled for potential confounding, or examined potential effect measure modification. Studies designed to investigate the youth alcohol–DVP link specifically, and whether results vary by individuals’ gender, developmental stage, or culture, are needed. PMID:22128086

Breast-feeding reduces the risk for childhood eczema.

PubMed

Kull, Inger; Böhme, Maria; Wahlgren, Carl-Fredrik; Nordvall, Lennart; Pershagen, Göran; Wickman, Magnus

2005-09-01

The evidence for a preventive effect of breast-feeding on the development of eczema in childhood remains controversial. To investigate the effect of breast-feeding in various phenotypes of eczema to 4 years. A birth cohort of 4089 children made up the study base. Data on breast-feeding, allergic symptoms, and potential confounders were obtained from questionnaires when the children were 2 months and 1, 2, and 4 years old. At 4 years, blood specific IgE was analyzed. Children with symptoms of eczema and asthma during the period of breast-feeding were excluded in most analyses on risk assessment of eczema and asthma, respectively, to avoid disease-related modification of exposure. Exclusive breast-feeding for >or=4 months reduced the risk for eczema at the age of 4 years (odds ratio [OR], 0.78; 95% CI, 0.63--0.96) irrespective of combination with asthma, sensitization to common allergens, or parental allergic disease. This decreased risk was most evident for children with onset of eczema during the first 2 years persisting to 4 years (OR, 0.59; 95% CI, 0.45--0.77). Among children with early-onset eczema, irrespective of persistency, followed by late onset of asthma or early-onset asthma irrespective of persistency, followed by late-onset eczema to 4 years, a protective effect of breast-feeding was also seen (OR, 0.48; 95% CI, 0.30--0.76). Breast-feeding 4 months or more reduces the risk for eczema and onset of the allergy march to age 4.

Smoking, physical exercise, BMI and late foetal death: a study within the Danish National Birth Cohort.

PubMed

Morales-Suárez-Varela, Maria; Nohr, Ellen A; Bech, Bodil H; Wu, Chunsen; Olsen, Jørn

2016-10-01

The aim of this paper was to estimate the effect of maternal and paternal smoking on foetal death (miscarriage and stillbirth) and to estimate potential interactions with physical exercise and pre-pregnancy body mass index. We selected 87,930 pregnancies from the population-based Danish National Birth Cohort. Information about lifestyle, occupational, medical and obstetric factors was obtained from a telephone interview and data on pregnancy outcomes came from the Danish population based registries. Cox regression was used to estimate the hazard ratios (adjusted for potential confounders) for predominantly late foetal death (miscarriage and stillbirth). An interaction contrast ratio was used to assess potential effect measure modification of smoking by physical exercise and body mass index. The adjusted hazard ratio of foetal death was 1.22 (95 % CI 1.02-1.46) for couples where both parents smoked compared to non-smoking parents (miscarriage: 1.18, 95 % CI 0.96-1.44; stillbirth: 1.32, 95 % CI 0.93-1.89). On the additive scale, we detected a small positive interaction for stillbirth between smoking and body mass index (overweight women). In conclusion, smoking during pregnancy was associated with a slightly higher hazard ratio for foetal death if both parents smoked. This study suggests that smoking may increase the negative effect of a high BMI on foetal death, but results were not statistically significant for the interaction between smoking and physical exercise.

Psychotic experiences and risk of self-injurious behaviour in the general population: a systematic review and meta-analysis.

PubMed

Honings, S; Drukker, M; Groen, R; van Os, J

2016-01-01

Recent studies suggest that psychotic experiences (PE) in the general population are associated with an increased risk of self-injurious behaviour. Both the magnitude of this association and the level of adjustment for confounders vary among studies. A meta-analysis was performed to integrate the available evidence. The influence of possible confounders, including variably defined depression, was assessed. A systematic review and meta-analysis was conducted including general population studies reporting on the risk of self-injurious behaviour in individuals with PE. Studies were identified by a systematic search strategy in Pubmed, PsycINFO and Embase. Reported effect sizes were extracted and meta-analytically pooled. The risk of self-injurious behaviour was 3.20 times higher in individuals with PE compared with those without. Subanalyses showed that PE were associated with self-harm, suicidal ideation as well as suicidal attempts. All studies had scope for considerable residual confounding; effect sizes adjusted for depression were significantly smaller than effect sizes unadjusted for depression. In the longitudinal studies, adjustment for psychopathology resulted in a 74% reduction in excess risk. PE are associated with self-injurious behaviour, suggesting they have potential as passive markers of suicidality. However, the association is confounded and several methodological issues remain, particularly how to separate PE from the full range of connected psychopathology in determining any specific association with self-injurious behaviour. Given evidence that PE represent an indicator of severity of non-psychotic psychopathology, the association between PE and self-injurious behaviour probably reflects a greater likelihood of self-injurious behaviour in more severe states of mental distress.

Pre-study feasibility and identifying sensitivity analyses for protocol pre-specification in comparative effectiveness research.

PubMed

Girman, Cynthia J; Faries, Douglas; Ryan, Patrick; Rotelli, Matt; Belger, Mark; Binkowitz, Bruce; O'Neill, Robert

2014-05-01

The use of healthcare databases for comparative effectiveness research (CER) is increasing exponentially despite its challenges. Researchers must understand their data source and whether outcomes, exposures and confounding factors are captured sufficiently to address the research question. They must also assess whether bias and confounding can be adequately minimized. Many study design characteristics may impact on the results; however, minimal if any sensitivity analyses are typically conducted, and those performed are post hoc. We propose pre-study steps for CER feasibility assessment and to identify sensitivity analyses that might be most important to pre-specify to help ensure that CER produces valid interpretable results.

Testing for gene-environment interaction under exposure misspecification.

PubMed

Sun, Ryan; Carroll, Raymond J; Christiani, David C; Lin, Xihong

2017-11-09

Complex interplay between genetic and environmental factors characterizes the etiology of many diseases. Modeling gene-environment (GxE) interactions is often challenged by the unknown functional form of the environment term in the true data-generating mechanism. We study the impact of misspecification of the environmental exposure effect on inference for the GxE interaction term in linear and logistic regression models. We first examine the asymptotic bias of the GxE interaction regression coefficient, allowing for confounders as well as arbitrary misspecification of the exposure and confounder effects. For linear regression, we show that under gene-environment independence and some confounder-dependent conditions, when the environment effect is misspecified, the regression coefficient of the GxE interaction can be unbiased. However, inference on the GxE interaction is still often incorrect. In logistic regression, we show that the regression coefficient is generally biased if the genetic factor is associated with the outcome directly or indirectly. Further, we show that the standard robust sandwich variance estimator for the GxE interaction does not perform well in practical GxE studies, and we provide an alternative testing procedure that has better finite sample properties. © 2017, The International Biometric Society.

An Improved Framework for Confound Regression and Filtering for Control of Motion Artifact in the Preprocessing of Resting-State Functional Connectivity Data

PubMed Central

Satterthwaite, Theodore D.; Elliott, Mark A.; Gerraty, Raphael T.; Ruparel, Kosha; Loughead, James; Calkins, Monica E.; Eickhoff, Simon B.; Hakonarson, Hakon; Gur, Ruben C.; Gur, Raquel E.; Wolf, Daniel H.

2013-01-01

Several recent reports in large, independent samples have demonstrated the influence of motion artifact on resting-state functional connectivity MRI (rsfc-MRI). Standard rsfc-MRI preprocessing typically includes regression of confounding signals and band-pass filtering. However, substantial heterogeneity exists in how these techniques are implemented across studies, and no prior study has examined the effect of differing approaches for the control of motion-induced artifacts. To better understand how in-scanner head motion affects rsfc-MRI data, we describe the spatial, temporal, and spectral characteristics of motion artifacts in a sample of 348 adolescents. Analyses utilize a novel approach for describing head motion on a voxelwise basis. Next, we systematically evaluate the efficacy of a range of confound regression and filtering techniques for the control of motion-induced artifacts. Results reveal that the effectiveness of preprocessing procedures on the control of motion is heterogeneous, and that improved preprocessing provides a substantial benefit beyond typical procedures. These results demonstrate that the effect of motion on rsfc-MRI can be substantially attenuated through improved preprocessing procedures, but not completely removed. PMID:22926292

The statistical pitfalls of the partially randomized preference design in non-blinded trials of psychological interventions.

PubMed

Gemmell, Isla; Dunn, Graham

2011-03-01

In a partially randomized preference trial (PRPT) patients with no treatment preference are allocated to groups at random, but those who express a preference receive the treatment of their choice. It has been suggested that the design can improve the external and internal validity of trials. We used computer simulation to illustrate the impact that an unmeasured confounder could have on the results and conclusions drawn from a PRPT. We generated 4000 observations ("patients") that reflected the distribution of the Beck Depression Index (DBI) in trials of depression. Half were randomly assigned to a randomized controlled trial (RCT) design and half were assigned to a PRPT design. In the RCT, "patients" were evenly split between treatment and control groups; whereas in the preference arm, to reflect patient choice, 87.5% of patients were allocated to the experimental treatment and 12.5% to the control. Unadjusted analyses of the PRPT data consistently overestimated the treatment effect and its standard error. This lead to Type I errors when the true treatment effect was small and Type II errors when the confounder effect was large. The PRPT design is not recommended as a method of establishing an unbiased estimate of treatment effect due to the potential influence of unmeasured confounders. Copyright © 2011 John Wiley & Sons, Ltd.

Confounding by dietary patterns of the inverse association between alcohol consumption and type 2 diabetes risk.

PubMed

Imamura, Fumiaki; Lichtenstein, Alice H; Dallal, Gerard E; Meigs, James B; Jacques, Paul F

2009-07-01

The ability to interpret epidemiologic observations is limited because of potential residual confounding by correlated dietary components. Dietary pattern analyses by factor analysis or partial least squares may overcome the limitation. To examine confounding by dietary pattern as well as standard risk factors and selected nutrients, the authors modeled the longitudinal association between alcohol consumption and 7-year risk of type 2 diabetes mellitus in 2,879 healthy adults enrolled in the Framingham Offspring Study (1991-2001) by Cox proportional hazard models. After adjustment for standard risk factors, consumers of > or =9.0 drinks/week had a significantly lower risk of type 2 diabetes mellitus compared with abstainers (hazard ratio = 0.47, 95% confidence interval (CI): 0.27, 0.81). Adjustment for selected nutrients had little effect on the hazard ratio, whereas adjustment for dietary pattern variables by factor analysis significantly shifted the hazard ratio away from null (hazard ratio = 0.33, 95% CI: 0.17, 0.64) by 40.0% (95% CI: 16.8, 57.0; P = 0.002). Dietary pattern variables by partial least squares showed similar results. Therefore, the observed inverse association, consistent with past studies, was confounded by dietary patterns, and this confounding was not captured by individual nutrient adjustment. The data suggest that alcohol intake, not dietary patterns associated with alcohol intake, is responsible for the observed inverse association with type 2 diabetes mellitus risk.

Review of methods for handling confounding by cluster and informative cluster size in clustered data

PubMed Central

Seaman, Shaun; Pavlou, Menelaos; Copas, Andrew

2014-01-01

Clustered data are common in medical research. Typically, one is interested in a regression model for the association between an outcome and covariates. Two complications that can arise when analysing clustered data are informative cluster size (ICS) and confounding by cluster (CBC). ICS and CBC mean that the outcome of a member given its covariates is associated with, respectively, the number of members in the cluster and the covariate values of other members in the cluster. Standard generalised linear mixed models for cluster-specific inference and standard generalised estimating equations for population-average inference assume, in general, the absence of ICS and CBC. Modifications of these approaches have been proposed to account for CBC or ICS. This article is a review of these methods. We express their assumptions in a common format, thus providing greater clarity about the assumptions that methods proposed for handling CBC make about ICS and vice versa, and about when different methods can be used in practice. We report relative efficiencies of methods where available, describe how methods are related, identify a previously unreported equivalence between two key methods, and propose some simple additional methods. Unnecessarily using a method that allows for ICS/CBC has an efficiency cost when ICS and CBC are absent. We review tools for identifying ICS/CBC. A strategy for analysis when CBC and ICS are suspected is demonstrated by examining the association between socio-economic deprivation and preterm neonatal death in Scotland. PMID:25087978

Directed acyclic graphs (DAGs): an aid to assess confounding in dental research.

PubMed

Merchant, Anwar T; Pitiphat, Waranuch

2002-12-01

Confounding, a special type of bias, occurs when an extraneous factor is associated with the exposure and independently affects the outcome. In order to get an unbiased estimate of the exposure-outcome relationship, we need to identify potential confounders, collect information on them, design appropriate studies, and adjust for confounding in data analysis. However, it is not always clear which variables to collect information on and adjust for in the analyses. Inappropriate adjustment for confounding can even introduce bias where none existed. Directed acyclic graphs (DAGs) provide a method to select potential confounders and minimize bias in the design and analysis of epidemiological studies. DAGs have been used extensively in expert systems and robotics. Robins (1987) introduced the application of DAGs in epidemiology to overcome shortcomings of traditional methods to control for confounding, especially as they related to unmeasured confounding. DAGs provide a quick and visual way to assess confounding without making parametric assumptions. We introduce DAGs, starting with definitions and rules for basic manipulation, stressing more on applications than theory. We then demonstrate their application in the control of confounding through examples of observational and cross-sectional epidemiological studies.

Probabilistic bias analysis in pharmacoepidemiology and comparative effectiveness research: a systematic review.

PubMed

Hunnicutt, Jacob N; Ulbricht, Christine M; Chrysanthopoulou, Stavroula A; Lapane, Kate L

2016-12-01

We systematically reviewed pharmacoepidemiologic and comparative effectiveness studies that use probabilistic bias analysis to quantify the effects of systematic error including confounding, misclassification, and selection bias on study results. We found articles published between 2010 and October 2015 through a citation search using Web of Science and Google Scholar and a keyword search using PubMed and Scopus. Eligibility of studies was assessed by one reviewer. Three reviewers independently abstracted data from eligible studies. Fifteen studies used probabilistic bias analysis and were eligible for data abstraction-nine simulated an unmeasured confounder and six simulated misclassification. The majority of studies simulating an unmeasured confounder did not specify the range of plausible estimates for the bias parameters. Studies simulating misclassification were in general clearer when reporting the plausible distribution of bias parameters. Regardless of the bias simulated, the probability distributions assigned to bias parameters, number of simulated iterations, sensitivity analyses, and diagnostics were not discussed in the majority of studies. Despite the prevalence and concern of bias in pharmacoepidemiologic and comparative effectiveness studies, probabilistic bias analysis to quantitatively model the effect of bias was not widely used. The quality of reporting and use of this technique varied and was often unclear. Further discussion and dissemination of the technique are warranted. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Drug safety analyses in a rheumatoid arthritis registry: application of different approaches regarding timing of exposure and confounder measurement.

PubMed

Solomon, Daniel H; Shadick, Nancy A; Weinblatt, Michael E; Zak, Agnes; Frits, Michelle; Franklin, Jessica M

2017-06-13

Patient registry data serves an increasing role in drug safety and comparative effectiveness research, but registry databases often do not contain confounder information measured at the same time that treatments begin. This study evaluated a set of approaches for estimating confounder values at treatment initiation using actual data from a rheumatoid arthritis (RA) registry to examine the risk of infection associated with different biologic DMARDs (bDMARDs). We examined the risk of infection associated with starting a TNF inhibitor (TNFi) versus any of the other non-TNFi bDMARDs. Different confounder assessment approaches were tested. All approaches were tested in Cox proportional hazard regression models that used a propensity score (PS). The confounder of interest was the disease activity score (DAS28-CRP). The confounder assessment approaches utilized different temporal relationships between the DAS28-CRP measurement and the start of the treatments of interest. We included 219 subjects with RA with 269 initiations of either a TNFi or a different bDMARD or both. Among this group, 305 infections were reported and confirmed through chart review. The hazard ratio (HR) for the risk of infection associated with use of a non-TNFi bDMARD ranged from 1.17 to 3.03 using 13 different approaches; only the approach with the highest HR produced results significantly different than one, but this approach included the fewest subjects and infections. The relative risk of infection for TNFi and other non-TNFi bDMARDs was similar using various approaches regarding which DAS28-CRP score should be used as the baseline measure in adjusted analyses.

The Effects of Constraints and Mastery on Mental and Physical Health: Conceptual and Methodological Considerations

PubMed Central

Infurna, Frank J.; Mayer, Axel

2015-01-01

Perceived control and health are closely interrelated in adulthood and old age. However, less is known regarding the differential implications of two facets of perceived control, constraints and mastery, for mental and physical health. Furthermore, a limitation of previous research testing the pathways linking perceived control to mental and physical health is that mediation was tested with cross-sectional designs and not in a longitudinal mediation design that accounts for temporal ordering and prior confounds. Using data from the Health and Retirement Study (HRS; n = 7,612, M age = 68, SD = 10.66; 59% women) we examined the effect of constraints and mastery on 4-year changes in mental and physical health and whether physical activity mediated such effects in a longitudinal mediation design. Using confirmatory factor analysis, we modeled the two-factor structure of perceived control that consisted of constraints and mastery. In our longitudinal mediation model, where we accounted for possible confounders (e.g., age, gender, education, neuroticism, conscientiousness, memory, and health conditions), constraints showed a stronger total effect on mental and physical health, than mastery, such that more constraints were associated with 4-year declines in mental and physical health. Physical activity did not mediate the effect of constraints and mastery on mental and physical health (indirect effect). In order to demonstrate the importance of a longitudinal mediation model that accounts for confounders, we also estimated the mediated effect using two models commonly used in the literature: cross-sectional mediation model and longitudinal mediation model without accounting for confounders. These mediation models indicated a spurious indirect effect that cannot be causally interpreted. Our results showcase that constraints and mastery have differential implications for mental and physical health, as well as how a longitudinal mediation design can illustrate (or not) pathways in developmental processes. Our discussion focuses on the conceptual and methodological implications of a two facet model of perceived control and the strengths of longitudinal mediation designs for testing conceptual models of human development. PMID:25938243

The effects of constraints and mastery on mental and physical health: Conceptual and methodological considerations.

PubMed

Infurna, Frank J; Mayer, Axel

2015-06-01

Perceived control and health are closely interrelated in adulthood and old age. However, less is known regarding the differential implications of 2 facets of perceived control, constraints and mastery, for mental and physical health. Furthermore, a limitation of previous research testing the pathways linking perceived control to mental and physical health is that mediation was tested with cross-sectional designs and not in a longitudinal mediation design that accounts for temporal ordering and prior confounds. Using data from the Health and Retirement Study (HRS; n = 7,612, M age = 68, SD = 10.66; 59% women) we examined the effect of constraints and mastery on 4-year changes in mental and physical health and whether physical activity mediated such effects in a longitudinal mediation design. Using confirmatory factor analysis, we modeled the 2-factor structure of perceived control that consisted of constraints and mastery. In our longitudinal mediation model, where we accounted for possible confounders (e.g., age, gender, education, neuroticism, conscientiousness, memory, and health conditions), constraints showed a stronger total effect on mental and physical health, than mastery, such that more constraints were associated with 4-year declines in mental and physical health. Physical activity did not mediate the effect of constraints and mastery on mental and physical health (indirect effect). To demonstrate the importance of a longitudinal mediation model that accounts for confounders, we also estimated the mediated effect using 2 models commonly used in the literature: cross-sectional mediation model and longitudinal mediation model without accounting for confounders. These mediation models indicated a spurious indirect effect that cannot be causally interpreted. Our results showcase that constraints and mastery have differential implications for mental and physical health, as well as how a longitudinal mediation design can illustrate (or not) pathways in developmental processes. Our discussion focuses on the conceptual and methodological implications of a 2 facet model of perceived control and the strengths of longitudinal mediation designs for testing conceptual models of human development. (c) 2015 APA, all rights reserved.

Effects on accidents of changes in the use of studded tyres in major cities in Norway: a long-term investigation.

PubMed

Elvik, Rune; Fridstrøm, Lasse; Kaminska, Joanna; Meyer, Sunniva Frislid

2013-05-01

This paper reports the findings of two studies made eleven years apart in Norway (Fridstrøm, 2000; Elvik and Kaminska, 2011) to evaluate effects on accidents of changes in the use of studded tyres in major cities in Norway. The first study covered the period from 1991 to 2000, the second study covered the period from 2002 to 2009. In both these periods, large changes in the percentage of cars using studded tyres were found in the cities that were included in the study. There was, in most cities, a tendency for the use of studded tyres to go down. Effects of these changes on injury accidents were evaluated by means of negative binomial regression models, using city and day as the unit of analysis, and including more than twenty explanatory variables in order to control for confounding factors. The effects of changes in the percentage of cars using studded tyres were well described by an accident modification function (dose-response curve), relating the size of changes in the number of accident to the size of the change in the use of studded tyres. Accidents during the season when the use of studded tyres is permitted were found to increase by about 5 percent if the use of studded tyres was reduced by 25 percentage points (e.g. from 50 to 25 percent) and to decline by about 2 percent when the use of studded tyres increased by 20 percentage points. Copyright © 2013 Elsevier Ltd. All rights reserved.

Does Using a Chair Backrest or Reducing Seated Hip Flexion Influence Trunk Muscle Activity and Discomfort? A Systematic Review.

PubMed

Curran, Máire; O'Sullivan, Leonard; O'Sullivan, Peter; Dankaerts, Wim; O'Sullivan, Kieran

2015-11-01

This paper systematically reviews the effect of chair backrests and reducing seated hip flexion on low back discomfort (LBD) and trunk muscle activation. Prolonged sitting commonly exacerbates low back pain (LBP). Several modifications to seated posture and chair design have been recommended, including using chairs with backrests and chairs that reduce hip flexion. Electronic databases were searched by two independent assessors. Part 1 of this review includes 26 studies comparing the effect of sitting with at least two different hip angles. In Part 2, seven studies that compared the effect of sitting with and without a backrest were eligible. Study quality was assessed using the PEDro scale. Significant confounding variables and a relatively small number of randomized controlled trials (RCTs) involving people with LBP complicates analysis of the results. There was moderate evidence that chair backrests reduce paraspinal muscle activation, and limited evidence that chair backrests reduce LBD. There was no evidence that chairs involving less hip flexion reduce LBP or LBD, or consistently alter trunk muscle activation. However, participants in several studies subjectively preferred the modified chairs involving less hip flexion. The limited evidence to support the use of chairs involving less seated hip flexion, or the effect of a backrest, is consistent with the limited evidence that other isolated chair design features can reduce LBP. LBP management is likely to require consideration of several factors in addition to sitting position. Larger RCTs involving people with LBP are required. © 2015, Human Factors and Ergonomics Society.

Pre-end-stage renal disease care not associated with dialysis facility neighborhood poverty in the United States.

PubMed

Plantinga, Laura C; Kim, Min; Goetz, Margarethe; Kleinbaum, David G; McClellan, William; Patzer, Rachel E

2014-01-01

Receipt of nephrology care prior to end-stage renal disease (ESRD) is a strong predictor of decreased mortality and morbidity, and neighborhood poverty may influence access to care. Our objective was to examine whether neighborhood poverty is associated with lack of pre-ESRD care at dialysis facilities. In a multi-level ecological study using geospatially linked 2007-2010 Dialysis Facility Report and 2006-2010 American Community Survey data, we examined whether high neighborhood poverty (≥20% of households in census tract living below poverty) was associated with dialysis facility-level lack of pre-ESRD care (percentage of patients with no nephrology care prior to dialysis start) in mixed-effects models, adjusting for facility and neighborhood confounders and allowing for neighborhood and regional random effects. Among the 5,184 facilities examined, 1,778 (34.3%) were located in a high-poverty area. Lack of pre-ESRD care was similar in poverty areas (30.8%) and other neighborhoods (29.6%). With adjustment, the absolute increase in percentage of patients at a facility with no pre-ESRD care associated with facility location in a poverty area versus other neighborhood was only 0.08% (95% CI -1.32, 1.47; p = 0.9). Potential effect modification by race and income inequality was detected. Despite previously reported detrimental effects of neighborhood poverty on health, facility neighborhood poverty was not associated with receipt of pre-ESRD care, suggesting no need to target interventions to increase access to pre-ESRD care at facilities in poorer geographic areas.

Pre-end-stage renal disease care not associated with dialysis facility neighborhood poverty in the United States

PubMed Central

Plantinga, Laura C.; Kim, Min; Goetz, Margarethe; Kleinbaum, David G.; McClellan, William; Patzer, Rachel E.

2014-01-01

Background Receipt of nephrology care prior to end-stage renal disease (ESRD) is a strong predictor of decreased mortality and morbidity, and neighborhood poverty may influence access to care. Our objective was to examine whether neighborhood poverty is associated with lack of pre-ESRD care at dialysis facilities. Methods In a multi-level ecological study using geospatially linked 2007-2010 Dialysis Facility Report and 2006-2010 American Community Survey data, we examined whether high neighborhood poverty (≥20% of households in census tract living below poverty) was associated with dialysis facility-level lack of pre-ESRD care (percentage of patients with no nephrology care prior to dialysis start) in mixed-effects models, adjusting for facility and neighborhood confounders and allowing for neighborhood and regional random effects. Results Among the 5184 facilities examined, 1778 (34.3%) were located in a high poverty area. Lack of pre-ESRD care was similar in poverty areas (30.8%) and other neighborhoods (29.6%). With adjustment, the absolute increase in percentage of patients at a facility with no pre-ESRD care associated with facility location in a poverty area vs. other neighborhood was only 0.08% (95% CI: -1.32%, 1.47%; P=0.9). Potential effect modification by race and income inequality was detected. Conclusion Despite previously reported detrimental effects of neighborhood poverty on health, facility neighborhood poverty was not associated with receipt of pre-ESRD care, suggesting no need to target interventions to increase access to pre-ESRD care at facilities in poorer geographic areas. PMID:24434854

Place and health in diabetes: the neighbourhood environment and risk of depression in adults with type 2 diabetes.

PubMed

Gariepy, G; Kaufman, J S; Blair, A; Kestens, Y; Schmitz, N

2015-07-01

Depression is a common co-illness in people with diabetes. Evidence suggests that the neighbourhood environment impacts the risk of depression, but few studies have investigated this effect in those with diabetes. We examined the effect of a range of neighbourhood characteristics on depression in people with Type 2 diabetes. This cohort study used five waves of data from 1298 participants with Type 2 diabetes from the Diabetes Health Study (2008-2013). We assessed depression using the Patient Health Questionnaire. We measured neighbourhood deprivation using census data; density of services using geospatial data; level of greenness using satellite imagery; and perceived neighbourhood characteristics using survey data. The effect of neighbourhood factors on risk of depression was estimated using survival analysis, adjusting for sociodemographic variables. We tested effect modification by age, sex and socio-economic characteristics using interaction terms. More physical activity facilities, cultural services and a greater level of greenness in the neighbourhood were associated with a lower risk of depression in our sample, even after adjusting for confounders. Material deprivation was associated with increased risk of depression, particularly in participants who were older or retired. Characteristics of neighbourhoods were associated with the risk of depression in people with Type 2 diabetes and there were vulnerable subgroups within this association. Clinicians are encouraged to consider the neighbourhood environment of their patients when assessing the risk of depression. Future intervention research is need for health policy recommendations. © 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.

Maternal mental health and social support: effect on childhood atopic and non-atopic asthma symptoms.

PubMed

Marques dos Santos, Letícia; Neves dos Santos, Darci; Rodrigues, Laura Cunha; Barreto, Maurício Lima

2012-11-01

Atopic and non-atopic asthma have distinct risk factors and immunological mechanisms, and few studies differentiate between the impacts of psychosocial factors on the prevalence of these disease phenotypes. The authors aimed to identify whether the effect of maternal mental health on prevalence of asthma symptoms differs between atopic and non-atopic children, taking into account family social support. This is a cross-sectional study of 1013 children participating in the Social Change Allergy and Asthma in Latin America project. Psychosocial data were collected through a household survey utilising Self-Reporting Questionnaire and Medical Outcome Study Social Support Scale. Socioeconomic and wheezing information was obtained through the questionnaire of the International Study of Allergy and Asthma in Childhood, and level of allergen-specific IgE was measured to identify atopy. Polytomous logistic regression was used to estimate the association between maternal mental health, social support and atopic and non-atopic wheezing. Effect modification was evaluated through stratified polytomous regression according to social support level. Maternal mental disorder had the same impact on atopic and non-atopic wheezing, even after adjusting for confounding variables. Affective, material and informational supports had protective effects on non-atopic asthma, and there is some evidence that social supports may act as a buffer for the impact of maternal mental disorder on non-atopic wheezing. Poor maternal mental health is positively associated with wheezing, independent of whether asthma is atopic or non-atopic, but perception of high levels of social support appears to buffer this relationship in non-atopic wheezers only.

A propensity scoring approach to characterizing the effects of maternal smoking during pregnancy on offspring's initial responses to cigarettes and alcohol

PubMed Central

Bidwell, L. Cinnamon; Palmer, Rohan H.C.; Brick, Leslie; Madden, Pamela A.F.; Heath, Andrew C.; Knopik, Valerie S.

2016-01-01

When examining the effects of prenatal exposure to maternal smoking during pregnancy (MSDP) on later offspring substance use, it is critical to consider familial environments confounded with MSDP. The purpose of this study was to examine the effect of MSDP on offspring's initial reactions to cigarettes and alcohol, which are indicators of future substance-use related problems. We tested these effects using two propensity score approaches (1) by controlling for confounding using the MSDP propensity score and 2) examining effects of MSDP across the MSDP risk distribution by grouping individuals into quantiles based on their MSDP propensity score. This study used data from 829 unrelated mothers with a reported lifetime history of smoking to determine the propensity for smoking only during their first trimester (MSDP-E) or throughout their entire pregnancy (MSDP-T). Propensity score analyses focused on the offspring (N=1616 female twins) of a large subset of these mothers. We examined the effects of levels of MSDP-E/T on offspring initial reactions to their first experiences with alcohol and cigarettes, across the distribution of liability for MSDP-E/T. MSDP-E/T emerged as significant predictors of offspring reactions to alcohol and cigarettes, but the effects were confounded by the familial liability for MSDP. Further, the unique MSDP effects that emerged were not uniform across the MSDP familial risk distribution. Our findings underscore the importance of properly accounting for correlated familial risk factors when examining the effects of MSDP on substance related outcomes. PMID:27098899

Ambient PM2.5 and stroke: effect modifiers and population attributable risk in six low- and middle-income countries

PubMed Central

Lin, Hualiang; Guo, Yanfei; Di, Qian; Zheng, Yang; Kowal, Paul; Xiao, Jianpeng; Liu, Tao; Li, Xing; Zeng, Weilin; Howard, Steven W.; Nelson, Erik J.; Qian, Zhengmin (Min); Ma, Wenjun; Wu, Fan

2017-01-01

Background and Purpose Short-term exposure to ambient fine particulate pollution (PM2.5) has been linked to increased stroke. Few studies, however, have examined the effects of long-term exposure. Methods A total of 45,625 participants were interviewed and included in this study, the participants came from the Study on Global AGEing and Adult Health, a prospective cohort in six low- and middle-income countries. Ambient PM2.5 levels were estimated for participants’ communities using satellite data. A multi-level logistic regression model was used to examine the association between long-term PM2.5 exposure and stroke. Potential effect modification by physical activity and consumption of fruit and vegetables was assessed. Results The odds of stroke were 1.13 (95% CI: 1.04, 1.22) for each 10 μg/m3 increase in PM2.5. This effect remained after adjustment for confounding factors including age, sex, smoking and indoor air pollution (adjusted OR=1.12, 95% CI: 1.04, 1.21). Further stratified analyses suggested that participants with higher levels of physical activity had greater odds of stroke, while those with higher consumption of fruit and vegetables had lower odds of stroke. These effects remained robust in sensitivity analyses. We further estimated that 6.55% (95% CI: 1.97%, 12.01%) of the stroke cases could be attributable to ambient PM2.5 in the study population. Conclusions This study suggests that ambient PM2.5 may increase the risk of stroke, and may be responsible for the astounding stroke burden in low- and middle-income countries. Additionally, greater physical activity may enhance, whereas greater consumption of fruit and vegetables may mitigate the effect. PMID:28386038

Ambient PM2.5 and Stroke: Effect Modifiers and Population Attributable Risk in Six Low- and Middle-Income Countries.

PubMed

Lin, Hualiang; Guo, Yanfei; Di, Qian; Zheng, Yang; Kowal, Paul; Xiao, Jianpeng; Liu, Tao; Li, Xing; Zeng, Weilin; Howard, Steven W; Nelson, Erik J; Qian, Zhengmin; Ma, Wenjun; Wu, Fan

2017-05-01

Short-term exposure to ambient fine particulate pollution (PM 2.5 ) has been linked to increased stroke. Few studies, however, have examined the effects of long-term exposure. A total of 45 625 participants were interviewed and included in this study, the participants came from the Study on Global Ageing and Adult Health, a prospective cohort in 6 low- and middle-income countries. Ambient PM 2.5 levels were estimated for participants' communities using satellite data. A multilevel logistic regression model was used to examine the association between long-term PM 2.5 exposure and stroke. Potential effect modification by physical activity and consumption of fruit and vegetables was assessed. The odds of stroke were 1.13 (95% confidence interval, 1.04-1.22) for each 10 μg/m 3 increase in PM 2.5 . This effect remained after adjustment for confounding factors including age, sex, smoking, and indoor air pollution (adjusted odds ratio=1.12; 95% confidence interval, 1.04-1.21). Further stratified analyses suggested that participants with higher levels of physical activity had greater odds of stroke, whereas those with higher consumption of fruit and vegetables had lower odds of stroke. These effects remained robust in sensitivity analyses. We further estimated that 6.55% (95% confidence interval, 1.97%-12.01%) of the stroke cases could be attributable to ambient PM 2.5 in the study population. This study suggests that ambient PM 2.5 may increase the risk of stroke and may be responsible for the astounding stroke burden in low- and middle-income countries. In addition, greater physical activity may enhance, whereas greater consumption of fruit and vegetables may mitigate the effect. © 2017 American Heart Association, Inc.

WHAT TO DO IF THERE IS NO REFERENCE SYSTEM

EPA Science Inventory

Efficient management and regulation of anthropogenic point source inputs requires a demonstrated and measurable ecological effect. In all ecosystems, the evaluation of anthropogenic effects is confounded by the effects of naturally existing environmental factors and river nonpoin...

Hepatic fat quantification: a prospective comparison of magnetic resonance spectroscopy and analysis methods for chemical-shift gradient echo magnetic resonance imaging with histologic assessment as the reference standard.

PubMed

Kang, Bo-Kyeong; Yu, Eun Sil; Lee, Seung Soo; Lee, Youngjoo; Kim, Namkug; Sirlin, Claude B; Cho, Eun Yoon; Yeom, Suk Keu; Byun, Jae Ho; Park, Seong Ho; Lee, Moon-Gyu

2012-06-01

The aims of this study were to assess the confounding effects of hepatic iron deposition, inflammation, and fibrosis on hepatic steatosis (HS) evaluation by magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) and to assess the accuracies of MRI and MRS for HS evaluation, using histology as the reference standard. In this institutional review board-approved prospective study, 56 patients gave informed consents and underwent chemical-shift MRI and MRS of the liver on a 1.5-T magnetic resonance scanner. To estimate MRI fat fraction (FF), 4 analysis methods were used (dual-echo, triple-echo, multiecho, and multi-interference), and MRS FF was calculated with T2 correction. Degrees of HS, iron deposition, inflammation, and fibrosis were analyzed in liver resection (n = 37) and biopsy (n = 19) specimens. The confounding effects of histology on fat quantification were assessed by multiple linear regression analysis. Using the histologic degree of HS as the reference standard, the accuracies of each method in estimating HS and diagnosing an HS of 5% or greater were determined by linear regression and receiver operating characteristic analyses. Iron deposition significantly confounded estimations of FF by the dual-echo (P < 0.001) and triple-echo (P = 0.033) methods, whereas no histologic feature confounded the multiecho and multi-interference methods or MRS. The MRS (r = 0.95) showed the strongest correlation with histologic degree of HS, followed by the multiecho (r = 0.92), multi-interference (r = 0.91), triple-echo (r = 0.90), and dual-echo (r = 0.85) methods. For diagnosing HS, the areas under the curve tended to be higher for MRS (0.96) and the multiecho (0.95), multi-interference (0.95), and triple-echo (0.95) methods than for the dual-echo method (0.88) (P ≥ 0.13). The multiecho and multi-interference MRI methods and MRS can accurately quantify hepatic fat, with coexisting histologic abnormalities having no confounding effects.

Title: Studies on drug switchability showed heterogeneity in methodological approaches: a scoping review.

PubMed

Belleudi, Valeria; Trotta, Francesco; Vecchi, Simona; Amato, Laura; Addis, Antonio; Davoli, Marina

2018-05-16

Several drugs share the same therapeutic indication, including those undergoing patent expiration. Concerns on the interchangeability are frequent in clinical practice, challenging the evaluation of switchability through observational research. To conduct a scoping review of observational studies on drug switchability to identify methodological strategies adopted to deal with bias and confounding. We searched PubMed, EMBASE, and Web of Science (updated 1/31/2017) to identify studies evaluating switchability in terms of effectiveness/safety outcomes or compliance. Three reviewers independently screened studies extracting all characteristics. Strategies to address confounding, particularly, previous drug use and switching reasons were considered. All findings were summarized in descriptive analyses. Thirty-two studies, published in the last 10 years, met the inclusion criteria. Epilepsy, cardiovascular and rheumatology were the most frequently represented clinical areas. 75% of the studies reported data on effectiveness/safety outcomes. The most frequent study design was cohort (65.6%) followed by case-control (21.9%) and self-controlled (12.5%). Case-control and case-crossover studies showed homogeneous methodological strategies to deal with bias and confounding. Among cohort studies, the confounding associated with previous drug use was addressed introducing variables in multivariate model (47.3%) or selecting only adherent patients (14.3%). Around 30% of cohort studies did not report reasons for switching. In the remaining 70%, clinical parameters or previous occurrence of outcomes were measured to identify switching connected with lack of effectiveness or adverse events. This study represents a starting point for researchers and administrators who are approaching the investigation and assessment of issues related to interchangeability of drugs. Copyright © 2018. Published by Elsevier Inc.

A comparison of propensity score-based approaches to health service evaluation: a case study of a preoperative physician-led clinic for high-risk surgical patients.

PubMed

Pham, Clarabelle T; Gibb, Catherine L; Mittinty, Murthy N; Fitridge, Robert A; Marshall, Villis R; Karnon, Jonathan D

2016-10-01

A physician-led clinic for the preoperative optimization and management of high-risk surgical patients was implemented in a South Australian public hospital in 2008. This study aimed to estimate the costs and effects of the clinic using a mixed retrospective and prospective observational study design. Alternative propensity score estimation methods were applied to retrospective routinely collected administrative and clinical data, using weighted and matched cohorts. Supplementary survey-based prospective data were collected to inform the analysis of the retrospective data and reduce potential unmeasured confounding. Using weighted cohorts, clinic patients had a significantly longer mean length of stay and higher mean cost. With the matched cohorts, reducing the calliper width resulted in a shorter mean length of stay in the clinic group, but the costs remained significantly higher. The prospective data indicated potential unmeasured confounding in all analyses other than in the most tightly matched cohorts. The application of alternative propensity-based approaches to a large sample of retrospective data, supplemented with a smaller sample of prospective data, informed a pragmatic approach to reducing potential observed and unmeasured confounding in an evaluation of a physician-led preoperative clinic. The need to generate tightly matched cohorts to reduce the potential for unmeasured confounding indicates that significant uncertainty remains around the effects of the clinic. This study illustrates the value of mixed retrospective and prospective observational study designs but also underlines the need to prospectively plan for the evaluation of costs and effects alongside the implementation of significant service innovations. © 2016 John Wiley & Sons, Ltd.

Influence of GSTM1 and GSTT1 genotypes and confounding factors on the frequency of sister chromatid exchange and micronucleus among road construction workers.

PubMed

Kumar, Anil; Yadav, Anita; Giri, Shiv Kumar; Dev, Kapil; Gautam, Sanjeev Kumar; Gupta, Ranjan; Aggarwal, Neeraj

2011-07-01

In the present study, we have investigated the influence of polymorphism of GSTM1 and GSTT1 genes and confounding factors such as age, sex, exposure duration and consumption habits on cytogenetic biomarkers. Frequency of sister chromatid exchanges (SCEs), high frequency cell (HFC) and cytokinesis blocked micronuclei (CBMN) were evaluated in peripheral blood lymphocytes of 115 occupationally exposed road construction workers and 105 unexposed individuals. The distribution of null and positive genotypes of glutathione-S transferase gene was evaluated by multiplex PCR among control and exposed subjects. An increased frequency of CBMN (7.03±2.08); SCE (6.95±1.76) and HFC (6.28±1.69) were found in exposed subjects when compared to referent (CBMN - 3.35±1.10; SCE - 4.13±1.30 and HFC - 3.98±1.56). These results were found statistically significant at p<0.05. When the effect of confounding factors on the frequency of studied biomarkers was evaluated, a strong positive interaction was found. The individuals having GSTM1 and GSTT1 null genotypes had higher frequency of CBMN, SCE and HFC. The association between GSTM1 and GSTT1 genotypes and studied biomarkers was found statistically significant at p<0.05. Our findings suggest that individuals having null type of GST are more susceptible to cytogenetic damage by occupational exposure regardless of confounding factors. There is a significant effect of polymorphism of these genes on cytogenetic biomarkers which are considered as early effects of genotoxic carcinogens. Copyright © 2011 Elsevier Ltd. All rights reserved.

The prompted optional randomization trial: a new design for comparative effectiveness research.

PubMed

Flory, James; Karlawish, Jason

2012-12-01

Randomized controlled trials are the gold standard for medical evidence because randomization provides the best-known protection against confounding of results. Randomization has practical and ethical problems that limit the number of trials that can be conducted, however. A different method for collecting clinical data retains the statistically useful properties of randomization without incurring its practical and ethical challenges. A computerized prompt introduces a random element into clinical decision-making that can be instantly overridden if it conflicts with optimal patient care. This creates a weak form of randomization that still eliminates the effect of all confounders, can be carried out without disturbing routine clinical care, and arguably will not require research-grade informed consent.

Longterm management of Polycystic Ovarian Syndrome (PCOS).

PubMed

Bates, Gordon W; Legro, Richard S

2013-07-05

Polycystic Ovarian Syndrome (PCOS) has been associated with numerous reproductive and metabolic abnormalities. Despite tremendous advances in the management of reproductive dysfunction, insight into the metabolic implications of PCOS is limited by the lack of uniform diagnostic criteria, the heterogeneity of the condition and the presence of confounders including obesity. Obesity clearly has a role in long term health and may best predict both reproductive and metabolic dysfunction as well as negatively affect the response to treatment in women with PCOS. Diabetes, cardiovascular disease and cancer are also at the forefront of any risk assessment or comprehensive treatment strategy for these women. Lifestyle modifications including dietary changes, increased exercise and weight loss are appropriate first line interventions for many women with PCOS. Pharmaceuticals including metformin, lipid lowering agents and oral contraceptives should be tailored to the individual's risk profile and treatment goals. Copyright © 2012. Published by Elsevier Ireland Ltd.

Instrumental variables as bias amplifiers with general outcome and confounding.

PubMed

Ding, P; VanderWeele, T J; Robins, J M

2017-06-01

Drawing causal inference with observational studies is the central pillar of many disciplines. One sufficient condition for identifying the causal effect is that the treatment-outcome relationship is unconfounded conditional on the observed covariates. It is often believed that the more covariates we condition on, the more plausible this unconfoundedness assumption is. This belief has had a huge impact on practical causal inference, suggesting that we should adjust for all pretreatment covariates. However, when there is unmeasured confounding between the treatment and outcome, estimators adjusting for some pretreatment covariate might have greater bias than estimators without adjusting for this covariate. This kind of covariate is called a bias amplifier, and includes instrumental variables that are independent of the confounder, and affect the outcome only through the treatment. Previously, theoretical results for this phenomenon have been established only for linear models. We fill in this gap in the literature by providing a general theory, showing that this phenomenon happens under a wide class of models satisfying certain monotonicity assumptions. We further show that when the treatment follows an additive or multiplicative model conditional on the instrumental variable and the confounder, these monotonicity assumptions can be interpreted as the signs of the arrows of the causal diagrams.

The relationship between urinary tract infection during pregnancy and preeclampsia: causal, confounded or spurious?

PubMed

Karmon, Anatte; Sheiner, Eyal

2008-06-01

Preeclampsia is a major cause of maternal morbidity, although its precise etiology remains elusive. A number of studies suggest that urinary tract infection (UTI) during the course of gestation is associated with elevated risk for preeclampsia, while others have failed to prove such an association. In our medical center, pregnant women who were exposed to at least one UTI episode during pregnancy were 1.3 times more likely to have mild preeclampsia and 1.8 times more likely to have severe preeclampsia as compared to unexposed women. Our results are based on univariate analyses and are not adjusted for potential confounders. This editorial aims to discuss the relationship between urinary tract infection and preeclampsia, as well as examine the current problems regarding the interpretation of this association. Although the relationship between UTI and preeclampsia has been demonstrated in studies with various designs, carried-out in a variety of settings, the nature of this association is unclear. By taking into account timeline, dose-response effects, treatment influences, and potential confounders, as well as by neutralizing potential biases, future studies may be able to clarify the relationship between UTI and preeclampsia by determining if it is causal, confounded, or spurious.

Confounding and Statistical Significance of Indirect Effects: Childhood Adversity, Education, Smoking, and Anxious and Depressive Symptomatology.

PubMed

Sheikh, Mashhood Ahmed

2017-01-01

The life course perspective, the risky families model, and stress-and-coping models provide the rationale for assessing the role of smoking as a mediator in the association between childhood adversity and anxious and depressive symptomatology (ADS) in adulthood. However, no previous study has assessed the independent mediating role of smoking in the association between childhood adversity and ADS in adulthood. Moreover, the importance of mediator-response confounding variables has rarely been demonstrated empirically in social and psychiatric epidemiology. The aim of this paper was to (i) assess the mediating role of smoking in adulthood in the association between childhood adversity and ADS in adulthood, and (ii) assess the change in estimates due to different mediator-response confounding factors (education, alcohol intake, and social support). The present analysis used data collected from 1994 to 2008 within the framework of the Tromsø Study ( N = 4,530), a representative prospective cohort study of men and women. Seven childhood adversities (low mother's education, low father's education, low financial conditions, exposure to passive smoke, psychological abuse, physical abuse, and substance abuse distress) were used to create a childhood adversity score. Smoking status was measured at a mean age of 54.7 years (Tromsø IV), and ADS in adulthood was measured at a mean age of 61.7 years (Tromsø V). Mediation analysis was used to assess the indirect effect and the proportion of mediated effect (%) of childhood adversity on ADS in adulthood via smoking in adulthood. The test-retest reliability of smoking was good (Kappa: 0.67, 95% CI: 0.63; 0.71) in this sample. Childhood adversity was associated with a 10% increased risk of smoking in adulthood (Relative risk: 1.10, 95% CI: 1.03; 1.18), and both childhood adversity and smoking in adulthood were associated with greater levels of ADS in adulthood ( p < 0.001). Smoking in adulthood did not significantly mediate the association between childhood adversity and ADS in adulthood. However, when education was excluded as a mediator-response confounding variable, the indirect effect of childhood adversity on ADS in adulthood was statistically significant ( p < 0.05). This study shows that a careful inclusion of potential confounding variables is important when assessing mediation.

Confounding and Statistical Significance of Indirect Effects: Childhood Adversity, Education, Smoking, and Anxious and Depressive Symptomatology

PubMed Central

Sheikh, Mashhood Ahmed

2017-01-01

The life course perspective, the risky families model, and stress-and-coping models provide the rationale for assessing the role of smoking as a mediator in the association between childhood adversity and anxious and depressive symptomatology (ADS) in adulthood. However, no previous study has assessed the independent mediating role of smoking in the association between childhood adversity and ADS in adulthood. Moreover, the importance of mediator-response confounding variables has rarely been demonstrated empirically in social and psychiatric epidemiology. The aim of this paper was to (i) assess the mediating role of smoking in adulthood in the association between childhood adversity and ADS in adulthood, and (ii) assess the change in estimates due to different mediator-response confounding factors (education, alcohol intake, and social support). The present analysis used data collected from 1994 to 2008 within the framework of the Tromsø Study (N = 4,530), a representative prospective cohort study of men and women. Seven childhood adversities (low mother's education, low father's education, low financial conditions, exposure to passive smoke, psychological abuse, physical abuse, and substance abuse distress) were used to create a childhood adversity score. Smoking status was measured at a mean age of 54.7 years (Tromsø IV), and ADS in adulthood was measured at a mean age of 61.7 years (Tromsø V). Mediation analysis was used to assess the indirect effect and the proportion of mediated effect (%) of childhood adversity on ADS in adulthood via smoking in adulthood. The test-retest reliability of smoking was good (Kappa: 0.67, 95% CI: 0.63; 0.71) in this sample. Childhood adversity was associated with a 10% increased risk of smoking in adulthood (Relative risk: 1.10, 95% CI: 1.03; 1.18), and both childhood adversity and smoking in adulthood were associated with greater levels of ADS in adulthood (p < 0.001). Smoking in adulthood did not significantly mediate the association between childhood adversity and ADS in adulthood. However, when education was excluded as a mediator-response confounding variable, the indirect effect of childhood adversity on ADS in adulthood was statistically significant (p < 0.05). This study shows that a careful inclusion of potential confounding variables is important when assessing mediation. PMID:28824498

Anesthesia in Experimental Stroke Research

PubMed Central

Hoffmann, Ulrike; Sheng, Huaxin; Ayata, Cenk; Warner, David S.

2016-01-01

Anesthetics have enabled major advances in development of experimental models of human stroke. Yet their profound pharmacologic effects on neural function can confound the interpretation of experimental stroke research. Anesthetics have drug and dose-specific effects on cerebral blood flow and metabolism, neurovascular coupling, autoregulation, ischemic depolarizations, excitotoxicity, inflammation, neural networks, and numerous molecular pathways relevant for stroke outcome. Both pre- and post-conditioning properties have been described. Anesthetics also modulate systemic arterial blood pressure, lung ventilation, and thermoregulation, all of which may interact with the ischemic insult as well as the therapeutic interventions. These confounds present a dilemma. Here, we provide an overview of the anesthetic mechanisms of action and molecular and physiologic effects on factors relevant to stroke outcomes that can guide the choice and optimization of the anesthetic regimen in experimental stroke. PMID:27534542

Conditional Random Fields for Fast, Large-Scale Genome-Wide Association Studies

PubMed Central

Huang, Jim C.; Meek, Christopher; Kadie, Carl; Heckerman, David

2011-01-01

Understanding the role of genetic variation in human diseases remains an important problem to be solved in genomics. An important component of such variation consist of variations at single sites in DNA, or single nucleotide polymorphisms (SNPs). Typically, the problem of associating particular SNPs to phenotypes has been confounded by hidden factors such as the presence of population structure, family structure or cryptic relatedness in the sample of individuals being analyzed. Such confounding factors lead to a large number of spurious associations and missed associations. Various statistical methods have been proposed to account for such confounding factors such as linear mixed-effect models (LMMs) or methods that adjust data based on a principal components analysis (PCA), but these methods either suffer from low power or cease to be tractable for larger numbers of individuals in the sample. Here we present a statistical model for conducting genome-wide association studies (GWAS) that accounts for such confounding factors. Our method scales in runtime quadratic in the number of individuals being studied with only a modest loss in statistical power as compared to LMM-based and PCA-based methods when testing on synthetic data that was generated from a generalized LMM. Applying our method to both real and synthetic human genotype/phenotype data, we demonstrate the ability of our model to correct for confounding factors while requiring significantly less runtime relative to LMMs. We have implemented methods for fitting these models, which are available at http://www.microsoft.com/science. PMID:21765897

A stratification approach using logit-based models for confounder adjustment in the study of continuous outcomes.

PubMed

Tan, Chuen Seng; Støer, Nathalie C; Chen, Ying; Andersson, Marielle; Ning, Yilin; Wee, Hwee-Lin; Khoo, Eric Yin Hao; Tai, E-Shyong; Kao, Shih Ling; Reilly, Marie

2017-01-01

The control of confounding is an area of extensive epidemiological research, especially in the field of causal inference for observational studies. Matched cohort and case-control study designs are commonly implemented to control for confounding effects without specifying the functional form of the relationship between the outcome and confounders. This paper extends the commonly used regression models in matched designs for binary and survival outcomes (i.e. conditional logistic and stratified Cox proportional hazards) to studies of continuous outcomes through a novel interpretation and application of logit-based regression models from the econometrics and marketing research literature. We compare the performance of the maximum likelihood estimators using simulated data and propose a heuristic argument for obtaining the residuals for model diagnostics. We illustrate our proposed approach with two real data applications. Our simulation studies demonstrate that our stratification approach is robust to model misspecification and that the distribution of the estimated residuals provides a useful diagnostic when the strata are of moderate size. In our applications to real data, we demonstrate that parity and menopausal status are associated with percent mammographic density, and that the mean level and variability of inpatient blood glucose readings vary between medical and surgical wards within a national tertiary hospital. Our work highlights how the same class of regression models, available in most statistical software, can be used to adjust for confounding in the study of binary, time-to-event and continuous outcomes.

Is the Relation Between Ozone and Mortality Confounded by Chemical Components of Particulate Matter? Analysis of 7 Components in 57 US Communities

PubMed Central

Anderson, G. Brooke; Krall, Jenna R.; Peng, Roger D.; Bell, Michelle L.

2012-01-01

Epidemiologic studies have linked tropospheric ozone pollution and human mortality. Although research has shown that this relation is not confounded by particulate matter when measured by mass, little scientific evidence exists on whether confounding exists by chemical components of the particle mixture. Using mortality and particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5) component data from 57 US communities (2000–2005), the authors investigate whether the ozone-mortality relation is confounded by 7 components of PM2.5: sulfate, nitrate, silicon, elemental carbon, organic carbon matter, sodium ion, and ammonium. Together, these components constitute most PM2.5 mass in the United States. Estimates of the effect of ozone on mortality were almost identical before and after controlling for the 7 components of PM2.5 considered (mortality increase/10-ppb ozone increase, before and after controlling: ammonium, 0.34% vs. 0.35%; elemental carbon, 0.36% vs. 0.37%; nitrate, 0.27% vs. 0.26%; organic carbon matter, 0.34% vs. 0.31%; silicon, 0.36% vs. 0.37%; sodium ion, 0.21% vs. 0.18%; and sulfate, 0.35% vs. 0.38%). Additionally, correlations were weak between ozone and each particulate component across all communities. Previous research found that the ozone-mortality relation is not confounded by particulate matter measured by mass; this national study indicates that the relation is also robust to control for specific components of PM2.5. PMID:23043133

Mismeasurement and the resonance of strong confounders: correlated errors.

PubMed

Marshall, J R; Hastrup, J L; Ross, J S

1999-07-01

Confounding in epidemiology, and the limits of standard methods of control for an imperfectly measured confounder, have been understood for some time. However, most treatments of this problem are based on the assumption that errors of measurement in confounding and confounded variables are independent. This paper considers the situation in which a strong risk factor (confounder) and an inconsequential but suspected risk factor (confounded) are each measured with errors that are correlated; the situation appears especially likely to occur in the field of nutritional epidemiology. Error correlation appears to add little to measurement error as a source of bias in estimating the impact of a strong risk factor: it can add to, diminish, or reverse the bias induced by measurement error in estimating the impact of the inconsequential risk factor. Correlation of measurement errors can add to the difficulty involved in evaluating structures in which confounding and measurement error are present. In its presence, observed correlations among risk factors can be greater than, less than, or even opposite to the true correlations. Interpretation of multivariate epidemiologic structures in which confounding is likely requires evaluation of measurement error structures, including correlations among measurement errors.

Adaptation of metabolism and evaporative water loss along an aridity gradient.

PubMed Central

Tieleman, B Irene; Williams, Joseph B; Bloomer, Paulette

2003-01-01

Broad-scale comparisons of birds indicate the possibility of adaptive modification of basal metabolic rate (BMR) and total evaporative water loss (TEWL) in species from desert environments, but these might be confounded by phylogeny or phenotypic plasticity. This study relates variation in avian BMR and TEWL to a continuously varying measure of environment, aridity. We test the hypotheses that BMR and TEWL are reduced along an aridity gradient within the lark family (Alaudidae), and investigate the role of phylogenetic inertia. For 12 species of lark, BMR and TEWL decreased along a gradient of increasing aridity, a finding consistent with our proposals. We constructed a phylogeny for 22 species of lark based on sequences of two mitochondrial genes, and investigated whether phylogenetic affinity played a part in the correlation of phenotype and environment. A test for serial independence of the data for mass-corrected TEWL and aridity showed no influence of phylogeny on our findings. However, we did discover a significant phylogenetic effect in mass-corrected data for BMR, a result attributable to common phylogenetic history or to common ecological factors. A test of the relationship between BMR and aridity using phylogenetic independent constrasts was consistent with our previous analysis: BMR decreased with increasing aridity. PMID:12590762

Environmental Chemicals and Type 2 Diabetes: An Updated Systematic Review of the Epidemiologic Evidence

PubMed Central

Kuo, Chin-Chi; Moon, Katherine; Thayer, Kristina A.; Navas-Acien, Ana

2015-01-01

The burden of diabetes is increasing globally. Identifying novel preventable risk factors is an urgent need. In 2011, the U.S. National Toxicological Program (NTP) conducted a workshop to evaluate the epidemiologic and experimental evidence on the relationship of environmental chemicals with obesity, diabetes and metabolic syndrome. Although the evidence was insufficient to establish causality, the NTP workshop review identified an overall positive association between some environmental chemicals and diabetes. In this systematic review, our objective was to summarize the epidemiological research published since the NTP workshop. We identified a total of 29 articles (7 on arsenic, 3 on cadmium, 2 on mercury, 11 on persistent organic pollutants, 3 on phthalates and 4 on bisphenol A) including 7 prospective studies. Considering consistency, temporality, strength, dose-response, and biological plausibility (confounding), we concluded that the evidence is suggestive but not sufficient for a relationship between arsenic and persistent organic pollutants, and insufficient for mercury, phthalates and bisphenol A. For cadmium the epidemiologic evidence does not seem to suggest an association with diabetes. Important research questions include the need of additional prospective studies and the evaluation of the dose-response relationship, the role of joint exposures, and effect modification with other comorbidities and genetic variants. PMID:24114039

Effects of exposure to direct-to-consumer television advertising for statin drugs on food and exercise guilt.

PubMed

Kruger, Christopher; Niederdeppe, Jeff; Byrne, Sahara; Avery, Rosemary J

2015-09-01

Pharmaceutical direct-to-consumer advertising (DTCA) is widely prevalent on US television. This study tests the relationship between estimated exposure to DTCA for statin drugs, which often feature mixed messages about the efficacy of diet and exercise in reducing risk of cholesterol and heart disease, and guilty feelings regarding food and exercise. A series of repeated cross-sectional surveys of the US population between 2001 and 2007 (N=106,859 adults aged 18 and older) were combined with data on the frequency of DTCA appearances on national, cable, and local television during the same time period. Adjusting for potential confounders with ordinary least squares (OLS) regression, increased potential exposure to statin DTCA was associated with increased food guilt (in a dose-response pattern) and exercise guilt (in a threshold pattern). This study provides new evidence that DTCA has potential to influence emotional well-being as well as direct behavioral responses emphasized in previous academic research. Health practitioners should be prepared to encounter and counsel patients who are prompted by DTCA to feel guilty about their food and exercise behaviors, feelings which may impact the likelihood of adherence to prescribed behavioral modification for weight management. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Effects of tooth profile modification on dynamic responses of a high speed gear-rotor-bearing system

NASA Astrophysics Data System (ADS)

Hu, Zehua; Tang, Jinyuan; Zhong, Jue; Chen, Siyu; Yan, Haiyan

2016-08-01

A finite element node dynamic model of a high speed gear-rotor-bearing system considering the time-varying mesh stiffness, backlash, gyroscopic effect and transmission error excitation is developed. Different tooth profile modifications are introduced into the gear pair and corresponding time-varying mesh stiffness curves are obtained. Effects of the tooth profile modification on mesh stiffness are analyzed, and the natural frequencies and mode shapes of the gear-rotor-bearing transmission system are given. The dynamic responses with respect to a wide input speed region including dynamic factor, vibration amplitude near the bearing and dynamic transmission error are obtained by introducing the time-varying mesh stiffness in different tooth profile modification cases into the gear-rotor-bearing dynamic system. Effects of the tooth profile modification on the dynamic responses are studied in detail. The numerical simulation results show that both the short profile modification and the long profile modification can affect the mutation of the mesh stiffness when the number of engaging tooth pairs changes. A short profile modification with an appropriate modification amount can improve the dynamic property of the system in certain work condition.

Biomechanical and psychosocial exposures are independent risk factors for carpal tunnel syndrome: assessment of confounding using causal diagrams.

PubMed

Harris-Adamson, Carisa; Eisen, Ellen A; Neophytou, Andreas; Kapellusch, Jay; Garg, Arun; Hegmann, Kurt T; Thiese, Matthew S; Dale, Ann Marie; Evanoff, Bradley; Bao, Stephen; Silverstein, Barbara; Gerr, Fred; Burt, Susan; Rempel, David

2016-11-01

Between 2001 and 2010, six research groups conducted coordinated prospective studies of carpal tunnel syndrome (CTS) incidence among US workers from various industries to estimate exposure-response relationships. This analysis examined the presence and magnitude of confounding between biomechanical and workplace psychosocial factors and incidence of dominant-hand CTS. 1605 participants, without CTS at enrolment, were followed for up to 3.5 years (2471 person-years). Demographic information, medical history and workplace psychosocial stress measures were collected at baseline. Individual workplace biomechanical exposures were collected for each task and combined across the workweek using time-weighted averaging (TWA). CTS case criteria were based on symptoms and results of electrophysiological testing. HRs were estimated with Cox proportional hazard models. Confounding was assessed using causal diagrams and an empirical criterion of 10% or greater change in effect estimate magnitude. There were 109 incident CTS cases (IR=4.41/100 person-years; 6.7% cumulative incidence). The relationships between CTS and forceful repetition rate, % time forceful hand exertion and the Threshold Limit Value for Hand Activity Level (TLV-HAL) were slightly confounded by decision latitude with effect estimates being attenuated towards the null (10-14% change) after adjustment. The risk of CTS among participants reporting high job strain was attenuated towards the null by 14% after adjusting for the HAL Scale or the % time forceful hand exertions. Although attenuation of the relationships between CTS and some biomechanical and work psychosocial exposures was observed after adjusting for confounding, the magnitudes were small and confirmed biomechanical and work psychosocial exposures as independent risk factors for incident CTS. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

On causal interpretation of race in regressions adjusting for confounding and mediating variables

PubMed Central

VanderWeele, Tyler J.; Robinson, Whitney R.

2014-01-01

We consider several possible interpretations of the “effect of race” when regressions are run with race as an exposure variable, controlling also for various confounding and mediating variables. When adjustment is made for socioeconomic status early in a person’s life, we discuss under what contexts the regression coefficients for race can be interpreted as corresponding to the extent to which a racial inequality would remain if various socioeconomic distributions early in life across racial groups could be equalized. When adjustment is also made for adult socioeconomic status, we note how the overall racial inequality can be decomposed into the portion that would be eliminated by equalizing adult socioeconomic status across racial groups and the portion of the inequality that would remain even if adult socioeconomic status across racial groups were equalized. We also discuss a stronger interpretation of the “effect of race” (stronger in terms of assumptions) involving the joint effects of race-associated physical phenotype (e.g. skin color), parental physical phenotype, genetic background and cultural context when such variables are thought to be hypothetically manipulable and if adequate control for confounding were possible. We discuss some of the challenges with such an interpretation. Further discussion is given as to how the use of selected populations in examining racial disparities can additionally complicate the interpretation of the effects. PMID:24887159

Neuropsychological functioning in older people with type 2 diabetes: the effect of controlling for confounding factors.

PubMed

Asimakopoulou, K G; Hampson, S E; Morrish, N J

2002-04-01

Neuropsychological functioning was examined in a group of 33 older (mean age 62.40 +/- 9.62 years) people with Type 2 diabetes (Group 1) and 33 non-diabetic participants matched with Group 1 on age, sex, premorbid intelligence and presence of hypertension and cardio/cerebrovascular conditions (Group 2). Data statistically corrected for confounding factors obtained from the diabetic group were compared with the matched control group. The results suggested small cognitive deficits in diabetic people's verbal memory and mental flexibility (Logical Memory A and SS7). No differences were seen between the two samples in simple and complex visuomotor attention, sustained complex visual attention, attention efficiency, mental double tracking, implicit memory, and self-reported memory problems. These findings indicate minimal cognitive impairment in relatively uncomplicated Type 2 diabetes and demonstrate the importance of control and matching for confounding factors.

If it is published in the peer-reviewed literature, it must be true?

PubMed

Wagner, Louis K

2014-10-01

Epidemiological research correlating cancer rates in a population of patients with radiation doses from medical X-rays is fraught with confounding factors that obfuscate the likelihood that any positive relationship is causal. This is a review of four studies involving some of those confounding factors. Comparisons of findings with other studies not encumbered by similar confounding factors can enhance assertions of causation between medical X-rays and cancer rates. Even so, such assertions rest significantly on opinions of researchers regarding the degree of consistency between findings among various studies. The question as to what degree any findings truly represent cause and effect will likely still meet with controversy. The importance of these findings to medicine should therefore not lie in any controversy regarding causation, but in what the findings potentially mean with regard to benefit and risk for patients and the professional practice of medicine.

Maternal smoking during pregnancy and children's cognitive and physical development: a causal risk factor?

PubMed

Gilman, Stephen E; Gardener, Hannah; Buka, Stephen L

2008-09-01

There remains considerable debate regarding the effects of maternal smoking during pregnancy on children's growth and development. Evidence that exposure to maternal smoking during pregnancy is associated with numerous adverse outcomes is contradicted by research suggesting that these associations are spurious. The authors investigated the relation between maternal smoking during pregnancy and 14 developmental outcomes of children from birth through age 7 years, using data from the Collaborative Perinatal Project (1959-1974; n = 52,919). In addition to adjusting for potential confounders measured contemporaneously with maternal smoking, the authors fitted conditional fixed-effects models among siblings that controlled for unmeasured confounders. Results from the conditional analyses indicated a birth weight difference of -85.63 g associated with smoking of >or=20 cigarettes daily during pregnancy (95% confidence interval: -131.91, -39.34) and 2.73 times' higher odds of being overweight at age 7 years (95% confidence interval: 1.30, 5.71). However, the associations between maternal smoking and 12 other outcomes studied (including Apgar score, intelligence, academic achievement, conduct problems, and asthma) were entirely eliminated after adjustment for measured and unmeasured confounders. The authors conclude that the hypothesized effects of maternal smoking during pregnancy on these outcomes either are not present or are not distinguishable from a broader range of familial factors associated with maternal smoking.

African ancestry, lung function and the effect of genetics

PubMed Central

Wehrmeister, Fernando C.; Hartwig, Fernando P.; Perez-Padilla, Rogelio; Gigante, Denise P.; Barros, Fernando C.; Oliveira, Isabel O.; Ferreira, Gustavo D.; Horta, Bernardo L.

2015-01-01

African-Americans have smaller lung function compared with European-Americans. The aim of this study was to disentangle the contribution of genetics from other variables on lung function. A cohort was followed from birth to 30 years of age in Brazil. Several variables were collected: genomic analysis based on DNA; forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) obtained by spirometry; height measured by anthropometrists; and thorax circumference evaluated by photonic scanner. Crude and adjusted linear regression models were calculated according to African ancestry. The sample comprised 2869 participants out of 3701 members of the cohort. Males with higher African ancestry by DNA analysis had a smaller FEV1 (−0.13 L, 95% CI −0.23– −0.03 L) and FVC (−0.21 L, 95% CI −0.32– −0.09 L) compared with those with less African ancestry, having accounted for height, sitting to standing height ratio and other confounders. Similar effects were seen in females. After adjustment, ancestry remained significantly associated with lung function, but the large effect of adjustment for confounding among males (but not females) does not allow us to exclude the possibility that residual confounding may still account for these findings. PMID:25700383

Breath biomarkers for lung cancer detection and assessment of smoking related effects--confounding variables, influence of normalization and statistical algorithms.

PubMed

Kischkel, Sabine; Miekisch, Wolfram; Sawacki, Annika; Straker, Eva M; Trefz, Phillip; Amann, Anton; Schubert, Jochen K

2010-11-11

Up to now, none of the breath biomarkers or marker sets proposed for cancer recognition has reached clinical relevance. Possible reasons are the lack of standardized methods of sampling, analysis and data processing and effects of environmental contaminants. Concentration profiles of endogenous and exogenous breath markers were determined in exhaled breath of 31 lung cancer patients, 31 smokers and 31 healthy controls by means of SPME-GC-MS. Different correcting and normalization algorithms and a principal component analysis were applied to the data. Differences of exhalation profiles in cancer and non-cancer patients did not persist if physiology and confounding variables were taken into account. Smoking history, inspired substance concentrations, age and gender were recognized as the most important confounding variables. Normalization onto PCO2 or BSA or correction for inspired concentrations only partially solved the problem. In contrast, previous smoking behaviour could be recognized unequivocally. Exhaled substance concentrations may depend on a variety of parameters other than the disease under investigation. Normalization and correcting parameters have to be chosen with care as compensating effects may be different from one substance to the other. Only well-founded biomarker identification, normalization and data processing will provide clinically relevant information from breath analysis. 2010 Elsevier B.V. All rights reserved.

Reporting of research quality characteristics of studies published in 6 major clinical dental specialty journals.

PubMed

Pandis, Nikolaos; Polychronopoulou, Argy; Madianos, Phoebus; Makou, Margarita; Eliades, Theodore

2011-06-01

The objective of this article was to record reporting characteristics related to study quality of research published in major specialty dental journals with the highest impact factor (Journal of Endodontics, Journal of Oral and Maxillofacial Surgery, American Journal of Orthodontics and Dentofacial Orthopedics; Pediatric Dentistry, Journal of Clinical Periodontology, and International Journal of Prosthetic Dentistry). The included articles were classified into the following 3 broad subject categories: (1) cross-sectional (snap-shot), (2) observational, and (3) interventional. Multinomial logistic regression was conducted for effect estimation using the journal as the response and randomization, sample calculation, confounding discussed, multivariate analysis, effect measurement, and confidence intervals as the explanatory variables. The results showed that cross-sectional studies were the dominant design (55%), whereas observational investigations accounted for 13%, and interventions/clinical trials for 32%. Reporting on quality characteristics was low for all variables: random allocation (15%), sample size calculation (7%), confounding issues/possible confounders (38%), effect measurements (16%), and multivariate analysis (21%). Eighty-four percent of the published articles reported a statistically significant main finding and only 13% presented confidence intervals. The Journal of Clinical Periodontology showed the highest probability of including quality characteristics in reporting results among all dental journals. Copyright © 2011 Elsevier Inc. All rights reserved.

Super learning to hedge against incorrect inference from arbitrary parametric assumptions in marginal structural modeling.

PubMed

Neugebauer, Romain; Fireman, Bruce; Roy, Jason A; Raebel, Marsha A; Nichols, Gregory A; O'Connor, Patrick J

2013-08-01

Clinical trials are unlikely to ever be launched for many comparative effectiveness research (CER) questions. Inferences from hypothetical randomized trials may however be emulated with marginal structural modeling (MSM) using observational data, but success in adjusting for time-dependent confounding and selection bias typically relies on parametric modeling assumptions. If these assumptions are violated, inferences from MSM may be inaccurate. In this article, we motivate the application of a data-adaptive estimation approach called super learning (SL) to avoid reliance on arbitrary parametric assumptions in CER. Using the electronic health records data from adults with new-onset type 2 diabetes, we implemented MSM with inverse probability weighting (IPW) estimation to evaluate the effect of three oral antidiabetic therapies on the worsening of glomerular filtration rate. Inferences from IPW estimation were noticeably sensitive to the parametric assumptions about the associations between both the exposure and censoring processes and the main suspected source of confounding, that is, time-dependent measurements of hemoglobin A1c. SL was successfully implemented to harness flexible confounding and selection bias adjustment from existing machine learning algorithms. Erroneous IPW inference about clinical effectiveness because of arbitrary and incorrect modeling decisions may be avoided with SL. Copyright © 2013 Elsevier Inc. All rights reserved.

Stratification for the propensity score compared with linear regression techniques to assess the effect of treatment or exposure.

PubMed

Senn, Stephen; Graf, Erika; Caputo, Angelika

2007-12-30

Stratifying and matching by the propensity score are increasingly popular approaches to deal with confounding in medical studies investigating effects of a treatment or exposure. A more traditional alternative technique is the direct adjustment for confounding in regression models. This paper discusses fundamental differences between the two approaches, with a focus on linear regression and propensity score stratification, and identifies points to be considered for an adequate comparison. The treatment estimators are examined for unbiasedness and efficiency. This is illustrated in an application to real data and supplemented by an investigation on properties of the estimators for a range of underlying linear models. We demonstrate that in specific circumstances the propensity score estimator is identical to the effect estimated from a full linear model, even if it is built on coarser covariate strata than the linear model. As a consequence the coarsening property of the propensity score-adjustment for a one-dimensional confounder instead of a high-dimensional covariate-may be viewed as a way to implement a pre-specified, richly parametrized linear model. We conclude that the propensity score estimator inherits the potential for overfitting and that care should be taken to restrict covariates to those relevant for outcome. Copyright (c) 2007 John Wiley & Sons, Ltd.

Effect of deformation on the structural state of piracetam

NASA Astrophysics Data System (ADS)

Kanunnikova, O. M.; Mikhailova, S. S.; Karban', O. V.; Mukhgalin, V. V.; Aksenova, V. V.; Sen'kovskii, B. V.; Pechina, E. A.; Lad'yanov, V. I.

2016-04-01

The effect of various deformation actions on the structure-phase transformations in piracetam of modifications I and II with a sodium acetate addition is studied. Mechanical activation and pressing are shown to cause the polymorphic transformation of modification I into modification II, and modification III forms predominantly during severe plastic deformation by torsion. The structural difference between the piracetam molecules of modifications I and II is found to be retained in aqueous solutions.

Selection of higher order regression models in the analysis of multi-factorial transcription data.

PubMed

Prazeres da Costa, Olivia; Hoffman, Arthur; Rey, Johannes W; Mansmann, Ulrich; Buch, Thorsten; Tresch, Achim

2014-01-01

Many studies examine gene expression data that has been obtained under the influence of multiple factors, such as genetic background, environmental conditions, or exposure to diseases. The interplay of multiple factors may lead to effect modification and confounding. Higher order linear regression models can account for these effects. We present a new methodology for linear model selection and apply it to microarray data of bone marrow-derived macrophages. This experiment investigates the influence of three variable factors: the genetic background of the mice from which the macrophages were obtained, Yersinia enterocolitica infection (two strains, and a mock control), and treatment/non-treatment with interferon-γ. We set up four different linear regression models in a hierarchical order. We introduce the eruption plot as a new practical tool for model selection complementary to global testing. It visually compares the size and significance of effect estimates between two nested models. Using this methodology we were able to select the most appropriate model by keeping only relevant factors showing additional explanatory power. Application to experimental data allowed us to qualify the interaction of factors as either neutral (no interaction), alleviating (co-occurring effects are weaker than expected from the single effects), or aggravating (stronger than expected). We find a biologically meaningful gene cluster of putative C2TA target genes that appear to be co-regulated with MHC class II genes. We introduced the eruption plot as a tool for visual model comparison to identify relevant higher order interactions in the analysis of expression data obtained under the influence of multiple factors. We conclude that model selection in higher order linear regression models should generally be performed for the analysis of multi-factorial microarray data.

Obesity disproportionately impacts lung volumes, airflow and exhaled nitric oxide in children.

PubMed

Yao, Tsung-Chieh; Tsai, Hui-Ju; Chang, Su-Wei; Chung, Ren-Hua; Hsu, Jing-Ya; Tsai, Ming-Han; Liao, Sui-Ling; Hua, Man-Chin; Lai, Shen-Hao; Chen, Li-Chen; Yeh, Kuo-Wei; Tseng, Yu-Lun; Lin, Wan-Chen; Chang, Su-Ching; Huang, Jing-Long

2017-01-01

The current literature focusing on the effect of obesity and overweight on lung function and fraction of exhaled nitric oxide (FeNO) in children, particularly among healthy children of non-European descent, remains controversial. Furthermore, whether the relationship of obesity and overweight with lung function and FeNO in children is modified by atopy is unclear. The objective of this study was to examine the effect of excess weight on lung function parameters and FeNO among Asian children, with a particular focus on exploring the potential effect modification by atopy. We investigated the effect of excess weight on lung function and FeNO in a population sample of 1,717 children aged 5 to 18 years and explored the potential modifying effect of atopy. There were positive associations of body mass index (BMI) z-score with forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), peak expiratory flow (PEF), and forced expiratory flow at 25-75% (FEF25-75) (all P<0.001), after controlling for confounders. The beta coefficient for FEV1 (0.084) was smaller than that for FVC (0.111). In contrast, a negative association was found between BMI z-score and FEV1/FVC ratio (P<0.001) and FeNO (P = 0.03). A consistent pattern of association for lung function variables was observed when stratifying by atopy. There was a negative association of BMI z-score with FeNO in atopic subjects (P = 0.006), but not in non-atopic subjects (P = 0.46). Excess weight disproportionately impacts lung volumes and airflow in children from the general population, independent of atopic status. Excess weight inversely affects FeNO in atopic but not in non-atopic children.

Sex-specific role of education on the associations of socioeconomic status indicators with obesity risk: A population-based study in South Korea

PubMed Central

Chung, Woojin; Lim, Seung-ji; Lee, Sunmi

2018-01-01

Background No study of obesity risk for people in developed countries has conducted a multi-dimensional analysis of the association of socioeconomic status with obesity. In this paper, we investigated if education functions as either a confounder or an effect modifier in the association of another socioeconomic status indicator with obesity. Methods This cross-sectional study analyzed data of an adult population sample (10,905 men and 14,580 women) from the Korea National Health and Nutrition Examination Survey (2010–2014). The study performed multivariate logistic regression analyses for three education levels and four indicators of socioeconomic status (i.e., marital status, residential area, occupation, and income). Results The overall prevalence of obesity was 38.1% in men and 29.1% in women (p < 0.001). In men, while education functioned as an effect modifier in the association between marital status and obesity (p for interaction = 0.006), it functioned as both a confounder (p < 0.001) and an effect modifier (p for interaction < 0.001) in the association between residential area and obesity. In contrast, in women, education functioned as a confounder in the association of residential area with obesity (p = 0.010). However, it functioned as both a confounder (p < 0.001) and an effect modifier (p for interaction = 0.012) in the association between income and obesity. A prediction showed that unlike in women, education was positively associated with obesity risk for some socioeconomic indicator groups in men; for example, in a rural resident group, a higher level of education increased the probability of being obese by 19.7%. Conclusions The present study suggests the need to examine sex-specific studies regarding the role of education on the association between other socioeconomic status indicators and obesity. This should be considered in planning education policies to reduce the risk of obesity. PMID:29298319

High birth weight and perinatal mortality among siblings: A register based study in Norway, 1967-2011.

PubMed

Kristensen, Petter; Keyes, Katherine M; Susser, Ezra; Corbett, Karina; Mehlum, Ingrid Sivesind; Irgens, Lorentz M

2017-01-01

Perinatal mortality according to birth weight has an inverse J-pattern. Our aim was to estimate the influence of familial factors on this pattern, applying a cohort sibling design. We focused on excess mortality among macrosomic infants (>2 SD above the mean) and hypothesized that the birth weight-mortality association could be explained by confounding shared family factors. We also estimated how the participant's deviation from mean sibling birth weight influenced the association. We included 1 925 929 singletons, born term or post-term to mothers with more than one delivery 1967-2011 registered in the Medical Birth Registry of Norway. We examined z-score birth weight and perinatal mortality in random-effects and sibling fixed-effects logistic regression models including measured confounders (e.g. maternal diabetes) as well as unmeasured shared family confounders (through fixed effects models). Birth weight-specific mortality showed an inverse J-pattern, being lowest (2.0 per 1000) at reference weight (z-score +1 to +2) and increasing for higher weights. Mortality in the highest weight category was 15-fold higher than reference. This pattern changed little in multivariable models. Deviance from mean sibling birth weight modified the mortality pattern across the birth weight spectrum: small and medium-sized infants had increased mortality when being smaller than their siblings, and large-sized infants had an increased risk when outweighing their siblings. Maternal diabetes and birth weight acted in a synergistic fashion with mortality among macrosomic infants in diabetic pregnancies in excess of what would be expected for additive effects. The inverse J-pattern between birth weight and mortality is not explained by measured confounders or unmeasured shared family factors. Infants are at particularly high mortality risk when their birth weight deviates substantially from their siblings. Sensitivity analysis suggests that characteristics related to maternal diabetes could be important in explaining the increased mortality among macrosomic infants.

Sex-specific role of education on the associations of socioeconomic status indicators with obesity risk: A population-based study in South Korea.

PubMed

Chung, Woojin; Kim, Jaeyeun; Lim, Seung-Ji; Lee, Sunmi

2018-01-01

No study of obesity risk for people in developed countries has conducted a multi-dimensional analysis of the association of socioeconomic status with obesity. In this paper, we investigated if education functions as either a confounder or an effect modifier in the association of another socioeconomic status indicator with obesity. This cross-sectional study analyzed data of an adult population sample (10,905 men and 14,580 women) from the Korea National Health and Nutrition Examination Survey (2010-2014). The study performed multivariate logistic regression analyses for three education levels and four indicators of socioeconomic status (i.e., marital status, residential area, occupation, and income). The overall prevalence of obesity was 38.1% in men and 29.1% in women (p < 0.001). In men, while education functioned as an effect modifier in the association between marital status and obesity (p for interaction = 0.006), it functioned as both a confounder (p < 0.001) and an effect modifier (p for interaction < 0.001) in the association between residential area and obesity. In contrast, in women, education functioned as a confounder in the association of residential area with obesity (p = 0.010). However, it functioned as both a confounder (p < 0.001) and an effect modifier (p for interaction = 0.012) in the association between income and obesity. A prediction showed that unlike in women, education was positively associated with obesity risk for some socioeconomic indicator groups in men; for example, in a rural resident group, a higher level of education increased the probability of being obese by 19.7%. The present study suggests the need to examine sex-specific studies regarding the role of education on the association between other socioeconomic status indicators and obesity. This should be considered in planning education policies to reduce the risk of obesity.

Negative control exposure studies in the presence of measurement error: implications for attempted effect estimate calibration

PubMed Central

Sanderson, Eleanor; Macdonald-Wallis, Corrie; Davey Smith, George

2018-01-01

Abstract Background Negative control exposure studies are increasingly being used in epidemiological studies to strengthen causal inference regarding an exposure-outcome association when unobserved confounding is thought to be present. Negative control exposure studies contrast the magnitude of association of the negative control, which has no causal effect on the outcome but is associated with the unmeasured confounders in the same way as the exposure, with the magnitude of the association of the exposure with the outcome. A markedly larger effect of the exposure on the outcome than the negative control on the outcome strengthens inference that the exposure has a causal effect on the outcome. Methods We investigate the effect of measurement error in the exposure and negative control variables on the results obtained from a negative control exposure study. We do this in models with continuous and binary exposure and negative control variables using analysis of the bias of the estimated coefficients and Monte Carlo simulations. Results Our results show that measurement error in either the exposure or negative control variables can bias the estimated results from the negative control exposure study. Conclusions Measurement error is common in the variables used in epidemiological studies; these results show that negative control exposure studies cannot be used to precisely determine the size of the effect of the exposure variable, or adequately adjust for unobserved confounding; however, they can be used as part of a body of evidence to aid inference as to whether a causal effect of the exposure on the outcome is present. PMID:29088358

Negative control exposure studies in the presence of measurement error: implications for attempted effect estimate calibration.

PubMed

Sanderson, Eleanor; Macdonald-Wallis, Corrie; Davey Smith, George

2018-04-01

Negative control exposure studies are increasingly being used in epidemiological studies to strengthen causal inference regarding an exposure-outcome association when unobserved confounding is thought to be present. Negative control exposure studies contrast the magnitude of association of the negative control, which has no causal effect on the outcome but is associated with the unmeasured confounders in the same way as the exposure, with the magnitude of the association of the exposure with the outcome. A markedly larger effect of the exposure on the outcome than the negative control on the outcome strengthens inference that the exposure has a causal effect on the outcome. We investigate the effect of measurement error in the exposure and negative control variables on the results obtained from a negative control exposure study. We do this in models with continuous and binary exposure and negative control variables using analysis of the bias of the estimated coefficients and Monte Carlo simulations. Our results show that measurement error in either the exposure or negative control variables can bias the estimated results from the negative control exposure study. Measurement error is common in the variables used in epidemiological studies; these results show that negative control exposure studies cannot be used to precisely determine the size of the effect of the exposure variable, or adequately adjust for unobserved confounding; however, they can be used as part of a body of evidence to aid inference as to whether a causal effect of the exposure on the outcome is present.

An independent component analysis confounding factor correction framework for identifying broad impact expression quantitative trait loci

PubMed Central

Ju, Jin Hyun; Crystal, Ronald G.

2017-01-01

Genome-wide expression Quantitative Trait Loci (eQTL) studies in humans have provided numerous insights into the genetics of both gene expression and complex diseases. While the majority of eQTL identified in genome-wide analyses impact a single gene, eQTL that impact many genes are particularly valuable for network modeling and disease analysis. To enable the identification of such broad impact eQTL, we introduce CONFETI: Confounding Factor Estimation Through Independent component analysis. CONFETI is designed to address two conflicting issues when searching for broad impact eQTL: the need to account for non-genetic confounding factors that can lower the power of the analysis or produce broad impact eQTL false positives, and the tendency of methods that account for confounding factors to model broad impact eQTL as non-genetic variation. The key advance of the CONFETI framework is the use of Independent Component Analysis (ICA) to identify variation likely caused by broad impact eQTL when constructing the sample covariance matrix used for the random effect in a mixed model. We show that CONFETI has better performance than other mixed model confounding factor methods when considering broad impact eQTL recovery from synthetic data. We also used the CONFETI framework and these same confounding factor methods to identify eQTL that replicate between matched twin pair datasets in the Multiple Tissue Human Expression Resource (MuTHER), the Depression Genes Networks study (DGN), the Netherlands Study of Depression and Anxiety (NESDA), and multiple tissue types in the Genotype-Tissue Expression (GTEx) consortium. These analyses identified both cis-eQTL and trans-eQTL impacting individual genes, and CONFETI had better or comparable performance to other mixed model confounding factor analysis methods when identifying such eQTL. In these analyses, we were able to identify and replicate a few broad impact eQTL although the overall number was small even when applying CONFETI. In light of these results, we discuss the broad impact eQTL that have been previously reported from the analysis of human data and suggest that considerable caution should be exercised when making biological inferences based on these reported eQTL. PMID:28505156

An independent component analysis confounding factor correction framework for identifying broad impact expression quantitative trait loci.

PubMed

Ju, Jin Hyun; Shenoy, Sushila A; Crystal, Ronald G; Mezey, Jason G

2017-05-01

Genome-wide expression Quantitative Trait Loci (eQTL) studies in humans have provided numerous insights into the genetics of both gene expression and complex diseases. While the majority of eQTL identified in genome-wide analyses impact a single gene, eQTL that impact many genes are particularly valuable for network modeling and disease analysis. To enable the identification of such broad impact eQTL, we introduce CONFETI: Confounding Factor Estimation Through Independent component analysis. CONFETI is designed to address two conflicting issues when searching for broad impact eQTL: the need to account for non-genetic confounding factors that can lower the power of the analysis or produce broad impact eQTL false positives, and the tendency of methods that account for confounding factors to model broad impact eQTL as non-genetic variation. The key advance of the CONFETI framework is the use of Independent Component Analysis (ICA) to identify variation likely caused by broad impact eQTL when constructing the sample covariance matrix used for the random effect in a mixed model. We show that CONFETI has better performance than other mixed model confounding factor methods when considering broad impact eQTL recovery from synthetic data. We also used the CONFETI framework and these same confounding factor methods to identify eQTL that replicate between matched twin pair datasets in the Multiple Tissue Human Expression Resource (MuTHER), the Depression Genes Networks study (DGN), the Netherlands Study of Depression and Anxiety (NESDA), and multiple tissue types in the Genotype-Tissue Expression (GTEx) consortium. These analyses identified both cis-eQTL and trans-eQTL impacting individual genes, and CONFETI had better or comparable performance to other mixed model confounding factor analysis methods when identifying such eQTL. In these analyses, we were able to identify and replicate a few broad impact eQTL although the overall number was small even when applying CONFETI. In light of these results, we discuss the broad impact eQTL that have been previously reported from the analysis of human data and suggest that considerable caution should be exercised when making biological inferences based on these reported eQTL.

Systematic Assessment of the Correlations of Household Income With Infectious, Biochemical, Physiological, and Environmental Factors in the United States, 1999–2006

PubMed Central

Patel, Chirag J.; Ioannidis, John P. A.; Cullen, Mark R.; Rehkopf, David H.

2015-01-01

A fuller understanding of the social epidemiology of disease requires an extended description of the relationships between social factors and health indicators in a systematic manner. In the present study, we investigated the correlations between income and 330 indicators of physiological, biochemical, and environmental health in participants in the US National Health and Nutrition Examination Survey (NHANES) (1999–2006). We combined data from 3 survey waves (n = 249–23,649 for various indicators) to search for linear and nonlinear (quadratic) correlates of income, and we validated significant (P < 0.00015) correlations in an independent testing data set (n = 255–7,855). We validated 66 out of 330 factors, including infectious (e.g., hepatitis A), biochemical (e.g., carotenoids, high-density lipoprotein cholesterol), physiological (e.g., upper leg length), and environmental (e.g., lead, cotinine) measures. We found only a modest amount of association modification by age, race/ethnicity, and gender, and there was no association modification for blacks. The present study is descriptive, not causal. We have shown in our systematic investigation the crucial place income has in relation to health risk factors. Future research can use these correlations to better inform theory and studies of pathways to disease, as well as utilize these findings to understand when confounding by income is most likely to introduce bias. PMID:25589242

Theoretical Basis of the Test-Negative Study Design for Assessment of Influenza Vaccine Effectiveness.

PubMed

Sullivan, Sheena G; Tchetgen Tchetgen, Eric J; Cowling, Benjamin J

2016-09-01

Influenza viruses undergo frequent antigenic changes. As a result, the viruses circulating change within and between seasons, and the composition of the influenza vaccine is updated annually. Thus, estimation of the vaccine's effectiveness is not constant across seasons. In order to provide annual estimates of the influenza vaccine's effectiveness, health departments have increasingly adopted the "test-negative design," using enhanced data from routine surveillance systems. In this design, patients presenting to participating general practitioners with influenza-like illness are swabbed for laboratory testing; those testing positive for influenza virus are defined as cases, and those testing negative form the comparison group. Data on patients' vaccination histories and confounder profiles are also collected. Vaccine effectiveness is estimated from the odds ratio comparing the odds of testing positive for influenza among vaccinated patients and unvaccinated patients, adjusting for confounders. The test-negative design is purported to reduce bias associated with confounding by health-care-seeking behavior and misclassification of cases. In this paper, we use directed acyclic graphs to characterize potential biases in studies of influenza vaccine effectiveness using the test-negative design. We show how studies using this design can avoid or minimize bias and where bias may be introduced with particular study design variations. © The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Employment effects of the Danish rehabilitation benefit.

PubMed

Pallesen, Palle B; Lynge, Elsebeth

2012-06-01

Social benefits aim to bring marginalised citizens back into the labour force. As benefits constitute a burden for tax payers, attention has been given to measure the effect. We used register data to assess the employment effect of rehabilitation benefit; the most liberal social benefit in Denmark. We used data on rehabilitation benefits paid during 1994-2004. In the study design, special care was given to overcome selection bias. We identified municipalities with most frequent (generous) and least frequent (stingy) use of rehabilitation benefit, controlling for confounders (step 1). From the generous municipalities, population subgroups where ≥10% received rehabilitation benefit (vulnerable group) were identified based on age, sex, education, cohabitation, children, and health (step 2). Outcome measure was employment rate in 2005 for vulnerable groups in generous municipalities compared with vulnerable groups in stingy municipalities, controlled for municipality employment rate, i.e. a ratio of ratios (step 3). Use of rehabilitation benefit varied 10-fold across the 271 Danish municipalities. The employment rate in 2005 for vulnerable groups was lower in generous than in stingy municipalities. The ratio of ratios was 0.915 (95% CI 0.888-0.945) for men and 0.919 (95% CI 0.896-0.942) for women. No positive employment effect of generous use of rehabilitation benefit was found. Although residual confounding cannot be excluded, it is nevertheless remarkable that the possibly positive effect of rehabilitation benefit was not sufficiently large to become visible, even in a study particularly designed to eliminate selection biases and to control for confounding.

How Confounder Strength Can Affect Allocation of Resources in Electronic Health Records.

PubMed

Lynch, Kristine E; Whitcomb, Brian W; DuVall, Scott L

2018-01-01

When electronic health record (EHR) data are used, multiple approaches may be available for measuring the same variable, introducing potentially confounding factors. While additional information may be gleaned and residual confounding reduced through resource-intensive assessment methods such as natural language processing (NLP), whether the added benefits offset the added cost of the additional resources is not straightforward. We evaluated the implications of misclassification of a confounder when using EHRs. Using a combination of simulations and real data surrounding hospital readmission, we considered smoking as a potential confounder. We compared ICD-9 diagnostic code assignment, which is an easily available measure but has the possibility of substantial misclassification of smoking status, with NLP, a method of determining smoking status that more expensive and time-consuming than ICD-9 code assignment but has less potential for misclassification. Classification of smoking status with NLP consistently produced less residual confounding than the use of ICD-9 codes; however, when minimal confounding was present, differences between the approaches were small. When considerable confounding is present, investing in a superior measurement tool becomes advantageous.

Long-term exposure to particulate matter, NO2 and the oxidative potential of particulates and diabetes prevalence in a large national health survey.

PubMed

Strak, Maciej; Janssen, Nicole; Beelen, Rob; Schmitz, Oliver; Vaartjes, Ilonca; Karssenberg, Derek; van den Brink, Carolien; Bots, Michiel L; Dijst, Martin; Brunekreef, Bert; Hoek, Gerard

2017-11-01

The evidence from observational epidemiological studies of a link between long-term air pollution exposure and diabetes prevalence and incidence is currently mixed. Some studies found the strongest associations of diabetes with fine particles, other studies with nitrogen dioxide and some studies found no associations. Our aim was to investigate associations between long-term exposure to multiple air pollutants and diabetes prevalence in a large national survey in the Netherlands. We performed a cross-sectional analysis using the 2012 Dutch national health survey to investigate the associations between the 2009 annual average concentrations of multiple air pollutants (PM 10 , PM 2.5 , PM 10-2.5 , PM 2.5 absorbance, OP DTT , OP ESR and NO 2 ) and diabetes prevalence, among 289,703 adults. Air pollution exposure was assessed by land use regression models. Diabetes was defined based on a combined measure of self-reported physician diagnosis and medication prescription from an external database. Using logistic regression, we adjusted for potential confounders, including neighborhood- and individual socio-economic status and lifestyle-related risk factors such as smoking habits, alcohol consumption, physical activity and BMI. After adjustment for potential confounders, all pollutants (except PM 2.5 ) were associated with diabetes prevalence. In two-pollutant models, NO 2 and OP DTT remained associated with increased diabetes prevalence. For NO 2 and OP DTT , single-pollutant ORs per interquartile range were 1.07 (95% CI: 1.05, 1.09) and 1.08 (95% CI: 1.05, 1.10), respectively. Stratified analysis showed no consistent effect modification by any of the included known diabetes risk factors. Long-term residential air pollution exposure was associated with diabetes prevalence in a large health survey in the Netherlands, strengthening the evidence of air pollution being an important diabetes risk factor. Most consistent associations were observed for NO 2 and oxidative potential of PM 2.5 measured by the DTT assay. The finding of an association with the oxidative potential of fine particles but not with PM 2.5 , suggests that particle composition may be important for a potential effect on diabetes. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Instrumental variable methods in comparative safety and effectiveness research.

PubMed

Brookhart, M Alan; Rassen, Jeremy A; Schneeweiss, Sebastian

2010-06-01

Instrumental variable (IV) methods have been proposed as a potential approach to the common problem of uncontrolled confounding in comparative studies of medical interventions, but IV methods are unfamiliar to many researchers. The goal of this article is to provide a non-technical, practical introduction to IV methods for comparative safety and effectiveness research. We outline the principles and basic assumptions necessary for valid IV estimation, discuss how to interpret the results of an IV study, provide a review of instruments that have been used in comparative effectiveness research, and suggest some minimal reporting standards for an IV analysis. Finally, we offer our perspective of the role of IV estimation vis-à-vis more traditional approaches based on statistical modeling of the exposure or outcome. We anticipate that IV methods will be often underpowered for drug safety studies of very rare outcomes, but may be potentially useful in studies of intended effects where uncontrolled confounding may be substantial.

Beyond greenspace: an ecological study of population general health and indicators of natural environment type and quality.

PubMed

Wheeler, Benedict W; Lovell, Rebecca; Higgins, Sahran L; White, Mathew P; Alcock, Ian; Osborne, Nicholas J; Husk, Kerryn; Sabel, Clive E; Depledge, Michael H

2015-04-30

Many studies suggest that exposure to natural environments ('greenspace') enhances human health and wellbeing. Benefits potentially arise via several mechanisms including stress reduction, opportunity and motivation for physical activity, and reduced air pollution exposure. However, the evidence is mixed and sometimes inconclusive. One explanation may be that "greenspace" is typically treated as a homogenous environment type. However, recent research has revealed that different types and qualities of natural environments may influence health and wellbeing to different extents. This ecological study explores this issue further using data on land cover type, bird species richness, water quality and protected or designated status to create small-area environmental indicators across Great Britain. Associations between these indicators and age/sex standardised prevalence of both good and bad health from the 2011 Census were assessed using linear regression models. Models were adjusted for indicators of socio-economic deprivation and rurality, and also investigated effect modification by these contextual characteristics. Positive associations were observed between good health prevalence and the density of the greenspace types, "broadleaf woodland", "arable and horticulture", "improved grassland", "saltwater" and "coastal", after adjusting for potential confounders. Inverse associations with bad health prevalence were observed for the same greenspace types, with the exception of "saltwater". Land cover diversity and density of protected/designated areas were also associated with good and bad health in the predicted manner. Bird species richness (an indicator of local biodiversity) was only associated with good health prevalence. Surface water quality, an indicator of general local environmental condition, was associated with good and bad health prevalence contrary to the manner expected, with poorer water quality associated with better population health. Effect modification by income deprivation and urban/rural status was observed for several of the indicators. The findings indicate that the type, quality and context of 'greenspace' should be considered in the assessment of relationships between greenspace and human health and wellbeing. Opportunities exist to further integrate approaches from ecosystem services and public health perspectives to maximise opportunities to inform policies for health and environmental improvement and protection.

Volunteering is associated with increased survival in able-bodied participants of the English Longitudinal Study of Ageing.

PubMed

Rogers, Nina Trivedy; Demakakos, Panayotes; Taylor, Mark Steven; Steptoe, Andrew; Hamer, Mark; Shankar, Aparna

2016-06-01

Volunteering has been linked to reduced mortality in older adults, but the mechanisms explaining this effect remain unclear. This study investigated whether volunteering is associated with increased survival in participants of the English Longitudinal Study of Ageing and whether differences in survival are modified by functional disabilities. A multivariate Cox Proportional Hazards model was used to estimate the association of volunteering with survival over a period of 10.9 years in 10 324 participants, while controlling for selected confounders. To investigate effect modification by disability, the analyses were repeated in participants with and without self-reported functional disabilities. Volunteering was associated with a reduced probability of death from all causes in univariate analyses (HR=0.65, CI 0.58 to 0.73, p<0.0001), but adjustment for covariates rendered this association non-significant (HR=0.90, CI 0.79 to 1.01, p=0.07). Able-bodied volunteers had significantly increased survival compared with able-bodied non-volunteers (HR=0.81, 95% CI 0.69 to 0.95, p=0.009). There was no significant survival advantage among disabled volunteers, compared with disabled non-volunteers (HR=1.06, CI 0.88 to 1.29, p=0.53). Volunteering is associated with reduced mortality in older adults in England, but this effect appears to be limited to volunteers who report no disabilities. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Cognitive Modification and Systematic Desensitization with Test Anxious High School Students.

ERIC Educational Resources Information Center

Leal, Lois L.; And Others

1981-01-01

Compares the relative effectiveness of cognitive modification and systematic desensitization with test anxious high school students (N=30). The systematic desensitization treatment appeared to be significantly more effective on the performance measure while cognitive modification was more effective on one of the self-report measures. (Author/JAC)

Experimental modification of interpretation bias about animal fear in young children: effects on cognition, avoidance behavior, anxiety vulnerability, and physiological responding.

PubMed

Lester, Kathryn J; Field, Andy P; Muris, Peter

2011-01-01

This study investigated the effects of experimentally modifying interpretation biases for children's cognitions, avoidance behavior, anxiety vulnerability, and physiological responding. Sixty-seven children (6-11 years) were randomly assigned to receive a positive or negative interpretation bias modification procedure to induce interpretation biases toward or away from threat about ambiguous situations involving Australian marsupials. Children rapidly learned to select outcomes of ambiguous situations, which were congruent with their assigned condition. Furthermore, following positive modification, children's threat biases about novel ambiguous situations significantly decreased, whereas threat biases significantly increased after negative modification. In response to a stress-evoking behavioral avoidance test, positive modification attenuated behavioral avoidance compared to negative modification. However, no significant effects of bias modification on anxiety vulnerability or physiological responses to this stress-evoking Behavioral Avoidance Task were observed.

Mental Health Following Acquisition of Disability in Adulthood--The Impact of Wealth.

PubMed

Kavanagh, Anne Marie; Aitken, Zoe; Krnjacki, Lauren; LaMontagne, Anthony Daniel; Bentley, Rebecca; Milner, Allison

2015-01-01

Acquisition of a disability in adulthood has been associated with a reduction in mental health. We tested the hypothesis that low wealth prior to disability acquisition is associated with a greater deterioration in mental health than for people with high wealth. We assess whether level of wealth prior to disability acquisition modifies this association using 12 waves of data (2001-2012) from the Household, Income and Labour Dynamics in Australia survey--a population-based cohort study of working-age Australians. Eligible participants reported at least two consecutive waves of disability preceded by at least two consecutive waves without disability (1977 participants, 13,518 observations). Fixed-effects linear regression was conducted with a product term between wealth prior to disability (in tertiles) and disability acquisition with the mental health component score of the SF-36 as the outcome. In models adjusted for time-varying confounders, there was evidence of negative effect measure modification by prior wealth of the association between disability acquisition and mental health (interaction term for lowest wealth tertile: -2.2 points, 95% CI -3.1 points, -1.2, p<0.001); low wealth was associated with a greater decline in mental health following disability acquisition (-3.3 points, 95% CI -4.0, -2.5) than high wealth (-1.1 points, 95% CI -1.7, -0.5). The findings suggest that low wealth prior to disability acquisition in adulthood results in a greater deterioration in mental health than among those with high wealth.

Mental Health Following Acquisition of Disability in Adulthood—The Impact of Wealth

PubMed Central

Kavanagh, Anne Marie; Aitken, Zoe; Krnjacki, Lauren; LaMontagne, Anthony Daniel; Bentley, Rebecca; Milner, Allison

2015-01-01

Background Acquisition of a disability in adulthood has been associated with a reduction in mental health. We tested the hypothesis that low wealth prior to disability acquisition is associated with a greater deterioration in mental health than for people with high wealth. Methods We assess whether level of wealth prior to disability acquisition modifies this association using 12 waves of data (2001–2012) from the Household, Income and Labour Dynamics in Australia survey–a population-based cohort study of working-age Australians. Eligible participants reported at least two consecutive waves of disability preceded by at least two consecutive waves without disability (1977 participants, 13,518 observations). Fixed-effects linear regression was conducted with a product term between wealth prior to disability (in tertiles) and disability acquisition with the mental health component score of the SF–36 as the outcome. Results In models adjusted for time-varying confounders, there was evidence of negative effect measure modification by prior wealth of the association between disability acquisition and mental health (interaction term for lowest wealth tertile: -2.2 points, 95% CI -3.1 points, -1.2, p<0.001); low wealth was associated with a greater decline in mental health following disability acquisition (-3.3 points, 95% CI -4.0, -2.5) than high wealth (-1.1 points, 95% CI -1.7, -0.5). Conclusion The findings suggest that low wealth prior to disability acquisition in adulthood results in a greater deterioration in mental health than among those with high wealth. PMID:26444990

Immune Alterations in Male and Female Mice after 2-Deoxy-D-Glucose Administration

NASA Technical Reports Server (NTRS)

Dreau, Didier; Morton, Darla S.; Foster, Mareva; Swiggett, Jeanene P.; Sonnenfeld, Gerald

1995-01-01

Administration of 2-deoxy-D-glucose (2-DG), an analog of glucose which inhibits glycolysis by competitive antagonism for phosphohexose isomerase, results in acute periods of intracellular glucoprivation and hyperglycemia resulting in hyperphagia. In addition to these changes in the carbohydrate metabolism, injection of 2-DG results in alterations of both the endocrine and neurological systems as suggested by modifications in oxytocin and glucocorticoid levels and norepinephrine production. Moreover, alterations of the immune response, such as a decrease in the in vitro proliferation of splenocytes after mitogen-stimulation, were observed in mice injected with 2-DG. Sex, genotype and environment are among the factors that may modulate effects of catecholamines and hypothalamo-pituitary-adrenal axis on these immune changes. Sexual dimorphism in immune function resulting from the effects of sex hormones on immune effector cells has been shown in both animals and humans. These observations have important implications, especially with regard to higher incidence of many autoimmune diseases in females. Evidence exists that reproductive hormones influence the immune system and increase the risk of immunologically related disorders in both animals and humans. Indeed, immunological responses in stressful situations may also be confounded by fluctuations of sex hormones especially in females. Lymphocyte distribution, cytoldne production, and the ability of lymphocyte to proliferate in vitro were analyzed in male and female mice to determine if sex influenced 2-DG immunomodulation. In addition, the influence of hormones, especially sex hormones, on these changes were evaluated.

Green Space and Depression during Pregnancy: Results from the Growing Up in New Zealand Study

PubMed Central

Nichani, Vikram; Bird, Amy; Grant, Cameron

2017-01-01

Background: Antenatal depression is an important contributor to poor maternal health experienced by some women. This study aimed to determine whether exposure to green space during pregnancy is associated with less depression, and whether this association is moderated by relevant factors, such as age, education, self-identified ethnicity, physical activity, residential rurality, and socioeconomic status. Methods: Health data were sourced from the cohort study “Growing Up in New Zealand” comprised of 6772 participants. Green space was estimated based on the proportion of green space within the Census Area Unit. Adjusted logistic mixed effect models were used to investigate the association between green space and antenatal depression after controlling for confounding variables. Results: Maternal exposure to green space were not associated with lower odds of antenatal depression. Indications of effect modifications due to relevant factors were not observed. Conclusions: This study did not determine an association between access to green space (measured based on the distance to the nearest green space) and antenatal depression. Therefore, a link between green space and antenatal depression was not established. For that reason, ensuring residential areas contain adequate green space may or may not be helpful in preventing antenatal depression and adverse health outcomes associated with this depression. More studies focusing on pregnant women in a range of social contexts, and considering both exposure and access to green space, are warranted to determine the relationships between green space and antenatal depression. PMID:28927014

Perceived fairness of pay among people with and without disabilities: a propensity score matched analysis of working Australians.

PubMed

Milner, Allison; Aitken, Zoe; Krnjacki, Lauren; Bentley, Rebecca; Blakely, Tony; LaMontagne, Anthony D; Kavanagh, Anne M

2015-09-01

Equity and fairness at work are associated with a range of organizational and health outcomes. Past research suggests that workers with disabilities experience inequity in the workplace. It is difficult to conclude whether the presence of disability is the reason for perceived unfair treatment due to the possible confounding of effect estimates by other demographic or socioeconomic factors. The data source was the Household, Income, and Labor Dynamics in Australia (HILDA) survey (2001-2012). Propensity for disability was calculated from logistic models including gender, age, education, country of birth, and father's occupational skill level as predictors. We then used nearest neighbor (on propensity score) matched analysis to match workers with disabilities to workers without disability. Results suggest that disability is independently associated with lower fairness of pay after controlling for confounding factors in the propensity score matched analysis; although results do suggest less than half a standard deviation difference, indicating small effects. Similar results were apparent in standard multivariable regression models and alternative propensity score analyses (stratification, covariate adjustment using the propensity score, and inverse probability of treatment weighting). Whilst neither multivariable regression nor propensity scores adjust for unmeasured confounding, and there remains the potential for other biases, similar results for the two methodological approaches to confounder adjustment provide some confidence of an independent association of disability with perceived unfairness of pay. Based on this, we suggest that the disparity in the perceived fairness of pay between people with and without disabilities may be explained by worse treatment of people with disabilities in the workplace.

The impact of in-work tax credit for families on self-rated health in adults: a cohort study of 6900 New Zealanders.

PubMed

Pega, Frank; Carter, Kristie; Kawachi, Ichiro; Davis, Peter; Gunasekara, Fiona Imlach; Lundberg, Olle; Blakely, Tony

2013-08-01

In-work tax credit (IWTC) for families, a welfare-to-work policy intervention, may impact health status by improving income and employment. Most studies estimate that IWTCs in the USA and the UK have no effect on self-rated health (SRH) and several other health outcomes, but these estimates may be biased by confounding. The current study estimates the impact of one such IWTC intervention (called In-Work Tax Credit) on SRH in adults in New Zealand, controlling more fully for confounding. We used data from seven waves (2002-2009) of the Survey of Family, Income and Employment, restricted to a balanced panel of adults in families. The exposures, eligibility for IWTC and the amount of IWTC a family was eligible for, were derived for each wave by applying government eligibility and entitlement criteria. The outcome, SRH, was collected annually. We used fixed effects regression analyses to eliminate time-invariant confounding and adjusted for measured time-varying confounders. Becoming eligible for IWTC was associated with no detectable change in SRH over the past year (β=0.001, 95% CI -0.022 to 0.023). A $1000 increase in the IWTC amount a family was eligible for increased SRH by 0.003 units (95% CI -0.005 to 0.011). This study found that becoming eligible for IWTC or a substantial increase in the IWTC amount was not associated with any detectable difference in SRH over the short term. Future research should investigate the impact of IWTC on health over the longer term.

Birth order has no effect on intelligence: a reply and extension of previous findings.

PubMed

Wichman, Aaron L; Rodgers, Joseph Lee; Maccallum, Robert C

2007-09-01

We address points raised by Zajonc and Sulloway, who reject findings showing that birth order has no effect on intelligence. Many objections to findings of null birth-order results seem to stem from a misunderstanding of the difference between study designs where birth order is confounded with true causal influences on intelligence across families and designs that control for some of these influences. We discuss some of the consequences of not appreciating the nature of this difference. When between-family confounds are controlled using appropriate study designs and techniques such as multilevel modeling, birth order is shown not to influence intelligence. We conclude with an empirical investigation of the replicability and generalizability of this approach.

Untangling the relative contribution of maltreatment severity and frequency to type of behavioral outcome in foster youth

PubMed Central

Jackson, Yo; Gabrielli, Joy; Fleming, Kandace; Makanui, P. Kalani; Tunno, Angela M.

2014-01-01

Within maltreatment research, type, frequency, and severity of abuse are often confounded and not always specifically documented. The result is that samples are often heterogeneous, and the role of components of maltreatment in predicting outcome is unclear. The purpose of the present study was to identify and test the potential unique role of type, frequency, and severity of maltreatment to elucidate each variable’s role in predicting outcome behavior. Data from 309 youth in foster care (ages 8–22) and their caregivers were collected using the Modified Maltreatment Classification System and the Behavioral Assessment System for Children, 2nd Edition (BASC2), to measure maltreatment exposure and behavioral outcome respectively. A measurement model of the BASC2 was completed to determine model fit within the sample data. A second confirmatory factor analysis (CFA) was completed to determine the unique contributions of frequency and severity of maltreatment across four types of abuse to externalizing, internalizing, and adaptive behavior. The result of the CFA determined good fit of the BASC2 to the sample data after a few modifications. The result of the second CFA indicated that the paths from severity to externalizing behavior and adaptive behavior (reverse loading) were significant. Paths from frequency of abuse were not predictive of behavioral outcome. Maltreatment is a complex construct and researchers are encouraged to avoid confounding components of abuse that may be differentially related to outcome behavior for youth. Untangling the multifaceted nature of abuse is important and may have implications for identifying specific outcomes for youth exposed to maltreatment. PMID:24612908

Adult Lifespan Cognitive Variability in the Cross-Sectional Cam-CAN Cohort

PubMed Central

Green, Emma; Shafto, Meredith A.; Matthews, Fiona E.; White, Simon R.

2015-01-01

This study examines variability across the age span in cognitive performance in a cross-sectional, population-based, adult lifespan cohort from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) study (n = 2680). A key question we highlight is whether using measures that are designed to detect age-related cognitive pathology may not be sensitive to, or reflective of, individual variability among younger adults. We present three issues that contribute to the debate for and against age-related increases in variability. Firstly, the need to formally define measures of central tendency and measures of variability. Secondly, in addition to the commonly addressed location-confounding (adjusting for covariates) there may exist changes in measures of variability due to confounder sub-groups. Finally, that increases in spread may be a result of floor or ceiling effects; where the measure is not sensitive enough at all ages. From the Cam-CAN study, a large population-based dataset, we demonstrate the existence of variability-confounding for the immediate episodic memory task; and show that increasing variance with age in our general cognitive measures is driven by a ceiling effect in younger age groups. PMID:26690191

Adult Lifespan Cognitive Variability in the Cross-Sectional Cam-CAN Cohort.

PubMed

Green, Emma; Shafto, Meredith A; Matthews, Fiona E; White, Simon R

2015-12-07

This study examines variability across the age span in cognitive performance in a cross-sectional, population-based, adult lifespan cohort from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) study (n = 2680). A key question we highlight is whether using measures that are designed to detect age-related cognitive pathology may not be sensitive to, or reflective of, individual variability among younger adults. We present three issues that contribute to the debate for and against age-related increases in variability. Firstly, the need to formally define measures of central tendency and measures of variability. Secondly, in addition to the commonly addressed location-confounding (adjusting for covariates) there may exist changes in measures of variability due to confounder sub-groups. Finally, that increases in spread may be a result of floor or ceiling effects; where the measure is not sensitive enough at all ages. From the Cam-CAN study, a large population-based dataset, we demonstrate the existence of variability-confounding for the immediate episodic memory task; and show that increasing variance with age in our general cognitive measures is driven by a ceiling effect in younger age groups.

Effect of breast feeding on intelligence in children: prospective study, sibling pairs analysis, and meta-analysis.

PubMed

Der, Geoff; Batty, G David; Deary, Ian J

2006-11-04

To assess the importance of maternal intelligence, and the effect of controlling for it and other important confounders, in the link between breast feeding and children's intelligence. Examination of the effect of breast feeding on cognitive ability and the impact of a range of potential confounders, in particular maternal IQ, within a national database. Additional analyses compared pairs of siblings from the sample who were and were not breast fed. The results are considered in the context of other studies that have also controlled for parental intelligence via meta-analysis. 1979 US national longitudinal survey of youth. Data on 5475 children, the offspring of 3161 mothers in the longitudinal survey. IQ in children measured by Peabody individual achievement test. The mother's IQ was more highly predictive of breastfeeding status than were her race, education, age, poverty status, smoking, the home environment, or the child's birth weight or birth order. One standard deviation advantage in maternal IQ more than doubled the odds of breast feeding. Before adjustment, breast feeding was associated with an increase of around 4 points in mental ability. Adjustment for maternal intelligence accounted for most of this effect. When fully adjusted for a range of relevant confounders, the effect was small (0.52) and non-significant (95% confidence interval -0.19 to 1.23). The results of the sibling comparisons and meta-analysis corroborated these findings. Breast feeding has little or no effect on intelligence in children. While breast feeding has many advantages for the child and mother, enhancement of the child's intelligence is unlikely to be among them.

Visual search for emotional expressions: Effect of stimulus set on anger and happiness superiority.

PubMed

Savage, Ruth A; Becker, Stefanie I; Lipp, Ottmar V

2016-01-01

Prior reports of preferential detection of emotional expressions in visual search have yielded inconsistent results, even for face stimuli that avoid obvious expression-related perceptual confounds. The current study investigated inconsistent reports of anger and happiness superiority effects using face stimuli drawn from the same database. Experiment 1 excluded procedural differences as a potential factor, replicating a happiness superiority effect in a procedure that previously yielded an anger superiority effect. Experiments 2a and 2b confirmed that image colour or poser gender did not account for prior inconsistent findings. Experiments 3a and 3b identified stimulus set as the critical variable, revealing happiness or anger superiority effects for two partially overlapping sets of face stimuli. The current results highlight the critical role of stimulus selection for the observation of happiness or anger superiority effects in visual search even for face stimuli that avoid obvious expression related perceptual confounds and are drawn from a single database.

Using ecological propensity score to adjust for missing confounders in small area studies.

PubMed

Wang, Yingbo; Pirani, Monica; Hansell, Anna L; Richardson, Sylvia; Blangiardo, Marta

2017-11-09

Small area ecological studies are commonly used in epidemiology to assess the impact of area level risk factors on health outcomes when data are only available in an aggregated form. However, the resulting estimates are often biased due to unmeasured confounders, which typically are not available from the standard administrative registries used for these studies. Extra information on confounders can be provided through external data sets such as surveys or cohorts, where the data are available at the individual level rather than at the area level; however, such data typically lack the geographical coverage of administrative registries. We develop a framework of analysis which combines ecological and individual level data from different sources to provide an adjusted estimate of area level risk factors which is less biased. Our method (i) summarizes all available individual level confounders into an area level scalar variable, which we call ecological propensity score (EPS), (ii) implements a hierarchical structured approach to impute the values of EPS whenever they are missing, and (iii) includes the estimated and imputed EPS into the ecological regression linking the risk factors to the health outcome. Through a simulation study, we show that integrating individual level data into small area analyses via EPS is a promising method to reduce the bias intrinsic in ecological studies due to unmeasured confounders; we also apply the method to a real case study to evaluate the effect of air pollution on coronary heart disease hospital admissions in Greater London. © The Author 2017. Published by Oxford University Press.

Computer-aided design of high-contact-ratio gears for minimum dynamic load and stress

NASA Technical Reports Server (NTRS)

Lin, Hsiang Hsi; Lee, Chinwai; Oswald, Fred B.; Townsend, Dennis P.

1990-01-01

A computer aided design procedure is presented for minimizing dynamic effects on high contact ratio gears by modification of the tooth profile. Both linear and parabolic tooth profile modifications of high contact ratio gears under various loading conditions are examined and compared. The effects of the total amount of modification and the length of the modification zone were systematically studied at various loads and speeds to find the optimum profile design for minimizing the dynamic load and the tooth bending stress. Parabolic profile modification is preferred over linear profile modification for high contact ratio gears because of its lower sensitivity to manufacturing errors. For parabolic modification, a greater amount of modification at the tooth tip and a longer modification zone are required. Design charts are presented for high contact ratio gears with various profile modifications operating under a range of loads. A procedure is illustrated for using the charts to find the optimum profile design.

Impact of pain reported during isometric quadriceps muscle strength testing in people with knee pain: data from the osteoarthritis initiative.

PubMed

Riddle, Daniel L; Stratford, Paul W

2011-10-01

Muscle force testing is one of the more common categories of diagnostic tests used in clinical practice. Clinicians have little evidence to guide interpretations of muscle force tests when pain is elicited during testing. The purpose of this study was to examine the construct validity of isometric quadriceps muscle strength tests by determining whether the relationship between maximal isometric quadriceps muscle strength and functional status was influenced by pain during isometric testing. A cross-sectional design was used. Data from the Osteoarthritis Initiative were used to identify 1,344 people with unilateral knee pain and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale scores of 1 or higher on the involved side. Measurements of maximal isometric quadriceps strength and ratings of pain during isometric testing were collected. Outcome variables were WOMAC physical function subscale, 20-m walk test, 400-m walk test, and a repeated chair stand test. Multiple regression models were used to determine whether pain during testing modified or confounded the relationship between strength and functional status. Pearson r correlations among the isometric quadriceps strength measures and the 4 outcome measures ranged from -.36 (95% confidence interval=-.41, -.31) for repeated chair stands to .36 (95% confidence interval=.31, .41) for the 20-m walk test. In the final analyses, neither effect modification nor confounding was found for the repeated chair stand test, the 20-m walk test, the 400-m walk test, or the WOMAC physical function subscale. Moderate or severe pain during testing was weakly associated with reduced strength, but mild pain was not. The disease spectrum was skewed toward mild or moderate symptoms, and the pain measurement scale used during muscle force testing was not ideal. Given that the spectrum of the sample was skewed toward mild or moderate symptoms and disease, the data suggest that isometric quadriceps muscle strength tests maintain their relationship with self-report or performance-based disability measures even when pain is elicited during testing.

Impact of Pain Reported During Isometric Quadriceps Muscle Strength Testing in People With Knee Pain: Data From the Osteoarthritis Initiative

PubMed Central

Stratford, Paul W.

2011-01-01

Background Muscle force testing is one of the more common categories of diagnostic tests used in clinical practice. Clinicians have little evidence to guide interpretations of muscle force tests when pain is elicited during testing. Objective The purpose of this study was to examine the construct validity of isometric quadriceps muscle strength tests by determining whether the relationship between maximal isometric quadriceps muscle strength and functional status was influenced by pain during isometric testing. Design A cross-sectional design was used. Methods Data from the Osteoarthritis Initiative were used to identify 1,344 people with unilateral knee pain and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale scores of 1 or higher on the involved side. Measurements of maximal isometric quadriceps strength and ratings of pain during isometric testing were collected. Outcome variables were WOMAC physical function subscale, 20-m walk test, 400-m walk test, and a repeated chair stand test. Multiple regression models were used to determine whether pain during testing modified or confounded the relationship between strength and functional status. Results Pearson r correlations among the isometric quadriceps strength measures and the 4 outcome measures ranged from −.36 (95% confidence interval=−.41, −.31) for repeated chair stands to .36 (95% confidence interval=.31, .41) for the 20-m walk test. In the final analyses, neither effect modification nor confounding was found for the repeated chair stand test, the 20-m walk test, the 400-m walk test, or the WOMAC physical function subscale. Moderate or severe pain during testing was weakly associated with reduced strength, but mild pain was not. Limitations The disease spectrum was skewed toward mild or moderate symptoms, and the pain measurement scale used during muscle force testing was not ideal. Conclusions Given that the spectrum of the sample was skewed toward mild or moderate symptoms and disease, the data suggest that isometric quadriceps muscle strength tests maintain their relationship with self-report or performance-based disability measures even when pain is elicited during testing. PMID:21835892

Effect Modification and Interaction Terms: It Takes Two to Tango.

PubMed

Jupiter, Daniel C

2016-01-01

In this Investigators' Corner I look more deeply into the previously discussed phenomenon of effect modification. I revisit an explanation and examples of the phenomenon and then examine how to account for it statistically. Specifically, I show, in detail, how to write a regression equation that includes interaction terms that account for the effect modification. Finally, I look at interpretation of regression coefficients both with and without the presence of effect modification, and the associated interaction terms. Copyright © 2016 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.

Risk Factors in Adolescent Hypertension

PubMed Central

Ewald, D. Rose; Haldeman, Lauren A.

2016-01-01

Hypertension is a complex and multifaceted disease, with many contributing factors. While diet and nutrition are important influences, the confounding effects of overweight and obesity, metabolic and genetic factors, racial and ethnic predispositions, socioeconomic status, cultural influences, growth rate, and pubertal stage have even more influence and make diagnosis quite challenging. The prevalence of hypertension in adolescents far exceeds the numbers who have been diagnosed; studies have found that 75% or more go undiagnosed. This literature review summarizes the challenges of blood pressure classification in adolescents, discusses the impact of these confounding influences, and identifies actions that will improve diagnosis and treatment outcomes. PMID:27335997

Task-independent effects are potential confounders in longitudinal imaging studies of learning in schizophrenia.

PubMed

Korostil, Michele; Fatima, Zainab; Kovacevic, Natasha; Menon, Mahesh; McIntosh, Anthony Randal

2016-01-01

Learning impairment is a core deficit in schizophrenia that impacts on real-world functioning and yet, elucidating its underlying neural basis remains a challenge. A key issue when interpreting learning-task experiments is that task-independent changes may confound interpretation of task-related signal changes in neuroimaging studies. The nature of these task-independent changes in schizophrenia is unknown. Therefore, we examined task-independent "time effects" in a group of participants with schizophrenia contrasted with healthy participants in a longitudinal fMRI learning-experiment designed to allow for examination of non-specific effects of time. Flanking the learning portions of the experiment with a task-of-no-interest allowed us to extract task-independent BOLD changes. Task-independent effects occurred in both groups, but were more robust in the schizophrenia group. There was a significant interaction effect between group and time in a distributed activity pattern that included inferior and superior temporal regions, frontal areas (left anterior insula and superior medial gyri), and parietal areas (posterior cingulate cortices and precuneus). This pattern showed task-independent linear decrease in BOLD amplitude over the two scanning sessions for the schizophrenia group, but showed either opposite effect or no activity changes for the control group. There was a trend towards a correlation between task-independent effects and the presence of more negative symptoms in the schizophrenia group. The strong interaction between group and time suggests that both the scanning experience as a whole and the transition between task-types evokes a different response in persons with schizophrenia and may confound interpretation of learning-related longitudinal imaging experiments if not explicitly considered.

An epidemiological and toxicological evaluation of the carcinogenicity of man-made vitreous fiber, with a consideration of coexposures.

PubMed

Wong, O; Musselman, R P

1994-01-01

Exposure to man-made mineral (or vitreous) fiber (MMMF or MMVF) is a potential health concern in both occupational and environmental settings. Previous epidemiologic studies have reported a small increase of lung cancer among workers exposed to MMVF. Most of these studies were cohort studies and lacked information on fiber concentration, occupational coexposures, and cigarette smoking. Some of the coexposures were known human lung carcinogens and could have accounted for the small lung cancer excess. In a recently completed epidemiologic case-control study of lung cancer in MMVF workers exposed to slag wool fibers, we analyzed lung cancer risk in relation to cumulative fiber exposure (concentration and duration) and smoking history and controlled for other coexposures such as asbestos contamination. No increased lung cancer risk with exposure to slag wool fibers was found. As expected, however, we detected a strong confounding effect of smoking. The findings from this epidemiologic study were consistent with the results of recently completed toxicologic studies, which found that slag wool fibers of dimension classically associated with tumor induction ("Stanton" fibers) do not stay in the lung in sufficient quantity or time to induce tumors in animals. In this paper we emphasize the importance of confounding effects due to coexposures and provide guidelines to estimate the magnitude of potential confounding effects of coexposures such as smoking.

Maternal Smoking during Pregnancy and Children's Cognitive and Physical Development: A Causal Risk Factor?

PubMed Central

Gardener, Hannah; Buka, Stephen L.

2008-01-01

There remains considerable debate regarding the effects of maternal smoking during pregnancy on children's growth and development. Evidence that exposure to maternal smoking during pregnancy is associated with numerous adverse outcomes is contradicted by research suggesting that these associations are spurious. The authors investigated the relation between maternal smoking during pregnancy and 14 developmental outcomes of children from birth through age 7 years, using data from the Collaborative Perinatal Project (1959–1974; n = 52,919). In addition to adjusting for potential confounders measured contemporaneously with maternal smoking, the authors fitted conditional fixed-effects models among siblings that controlled for unmeasured confounders. Results from the conditional analyses indicated a birth weight difference of −85.63 g associated with smoking of ≥20 cigarettes daily during pregnancy (95% confidence interval: −131.91, −39.34) and 2.73 times' higher odds of being overweight at age 7 years (95% confidence interval: 1.30, 5.71). However, the associations between maternal smoking and 12 other outcomes studied (including Apgar score, intelligence, academic achievement, conduct problems, and asthma) were entirely eliminated after adjustment for measured and unmeasured confounders. The authors conclude that the hypothesized effects of maternal smoking during pregnancy on these outcomes either are not present or are not distinguishable from a broader range of familial factors associated with maternal smoking. PMID:18653646

A weight modification sequential method for VSC-MTDC power system state estimation

NASA Astrophysics Data System (ADS)

Yang, Xiaonan; Zhang, Hao; Li, Qiang; Guo, Ziming; Zhao, Kun; Li, Xinpeng; Han, Feng

2017-06-01

This paper presents an effective sequential approach based on weight modification for VSC-MTDC power system state estimation, called weight modification sequential method. The proposed approach simplifies the AC/DC system state estimation algorithm through modifying the weight of state quantity to keep the matrix dimension constant. The weight modification sequential method can also make the VSC-MTDC system state estimation calculation results more ccurate and increase the speed of calculation. The effectiveness of the proposed weight modification sequential method is demonstrated and validated in modified IEEE 14 bus system.

Modification of Heat-Related Mortality in an Elderly Urban Population by Vegetation (Urban Green) and Proximity to Water (Urban Blue): Evidence from Lisbon, Portugal.

PubMed

Burkart, Katrin; Meier, Fred; Schneider, Alexandra; Breitner, Susanne; Canário, Paulo; Alcoforado, Maria João; Scherer, Dieter; Endlicher, Wilfried

2016-07-01

Urban populations are highly vulnerable to the adverse effects of heat, with heat-related mortality showing intra-urban variations that are likely due to differences in urban characteristics and socioeconomic status. We investigated the influence of urban green and urban blue, that is, urban vegetation and water bodies, on heat-related excess mortality in the elderly > 65 years old in Lisbon, Portugal, between 1998 and 2008. We used remotely sensed data and geographic information to determine the amount of urban vegetation and the distance to bodies of water (the Atlantic Ocean and the Tagus Estuary). Poisson generalized additive models were fitted, allowing for the interaction between equivalent temperature [universal thermal climate index (UTCI)] and quartiles of urban greenness [classified using the Normalized Difference Vegetation Index (NDVI)] and proximity to water (≤ 4 km vs. > 4 km), while adjusting for potential confounders. The association between mortality and a 1°C increase in UTCI above the 99th percentile (24.8°C) was stronger for areas in the lowest NDVI quartile (14.7% higher; 95% CI: 1.9, 17.5%) than for areas in the highest quartile (3.0%; 95% CI: 2.0, 4.0%). In areas > 4 km from water, a 1°C increase in UTCI above the 99th percentile was associated with a 7.1% increase in mortality (95% CI: 6.2, 8.1%), whereas in areas ≤ 4 km from water, the estimated increase in mortality was only 2.1% (95% CI: 1.2, 3.0%). Urban green and blue appeared to have a mitigating effect on heat-related mortality in the elderly population in Lisbon. Increasing the amount of vegetation may be a good strategy to counteract the adverse effects of heat in urban areas. Our findings also suggest potential benefits of urban blue that may be present several kilometers from a body of water. Burkart K, Meier F, Schneider A, Breitner S, Canário P, Alcoforado MJ, Scherer D, Endlicher W. 2016. Modification of heat-related mortality in an elderly urban population by vegetation (urban green) and proximity to water (urban blue): evidence from Lisbon, Portugal. Environ Health Perspect 124:927-934; http://dx.doi.org/10.1289/ehp.1409529.

Instrumental variable applications using nursing home prescribing preferences in comparative effectiveness research.

PubMed

Huybrechts, Krista F; Gerhard, Tobias; Franklin, Jessica M; Levin, Raisa; Crystal, Stephen; Schneeweiss, Sebastian

2014-08-01

Nursing home residents are of particular interest for comparative effectiveness research given their susceptibility to adverse treatment effects and systematic exclusion from trials. However, the risk of residual confounding because of unmeasured markers of declining health using conventional analytic methods is high. We evaluated the validity of instrumental variable (IV) methods based on nursing home prescribing preference to mitigate such confounding, using psychotropic medications to manage behavioral problems in dementia as a case study. A cohort using linked data from Medicaid, Medicare, Minimum Data Set, and Online Survey, Certification and Reporting for 2001-2004 was established. Dual-eligible patients ≥65 years who initiated psychotropic medication use after admission were selected. Nursing home prescribing preference was characterized using mixed-effects logistic regression models. The plausibility of IV assumptions was explored, and the association between psychotropic medication class and 180-day mortality was estimated. High-prescribing and low-prescribing nursing homes differed by a factor of 2. Each preference-based IV measure described a substantial proportion of variation in psychotropic medication choice (β(IV → treatment): 0.22-0.36). Measured patient characteristics were well balanced across patient groups based on instrument status (52% average reduction in Mahalanobis distance). There was no evidence that instrument status was associated with markers of nursing home quality of care. Findings indicate that IV analyses using nursing home prescribing preference may be a useful approach in comparative effectiveness studies, and should extend naturally to analyses including untreated comparison groups, which are of great scientific interest but subject to even stronger confounding. Copyright © 2014 John Wiley & Sons, Ltd.

Concurrent and Sustained Cumulative Effects of Adolescent Marijuana Use on Subclinical Psychotic Symptoms.

PubMed

Bechtold, Jordan; Hipwell, Alison; Lewis, David A; Loeber, Rolf; Pardini, Dustin

2016-08-01

Adolescents who regularly use marijuana may be at heightened risk of developing subclinical and clinical psychotic symptoms. However, this association could be explained by reverse causation or other factors. To address these limitations, the current study examined whether adolescents who engage in regular marijuana use exhibit a systematic increase in subclinical psychotic symptoms that persists during periods of sustained abstinence. The sample comprised 1,009 boys who were recruited in 1st and 7th grades. Self-reported frequency of marijuana use, subclinical psychotic symptoms, and several time-varying confounds (e.g., other substance use, internalizing/externalizing problems) were recorded annually from age 13 to 18. Fixed-effects (within-individual change) models examined whether adolescents exhibited an increase in their subclinical psychotic symptoms as a function of their recent and/or cumulative history of regular marijuana use and whether these effects were sustained following abstinence. Models controlled for all time-stable factors (default) and several time-varying covariates as potential confounds. For each year adolescent boys engaged in regular marijuana use, their expected level of subsequent subclinical psychotic symptoms rose by 21% and their expected odds of experiencing subsequent subclinical paranoia or hallucinations rose by 133% and 92%, respectively. The effect of prior regular marijuana use on subsequent subclinical psychotic symptoms persisted even when adolescents stopped using marijuana for a year. These effects were after controlling for all time-stable and several time-varying confounds. No support was found for reverse causation. These results suggest that regular marijuana use may significantly increase the risk that an adolescent will experience persistent subclinical psychotic symptoms.

Effect of Carboxymethylation on the Rheological Properties of Hyaluronan

PubMed Central

Wendling, Rian J.; Christensen, Amanda M.; Quast, Arthur D.; Atzet, Sarah K.; Mann, Brenda K.

2016-01-01

Chemical modifications made to hyaluronan to enable covalent crosslinking to form a hydrogel or to attach other molecules may alter the physical properties as well, which have physiological importance. Here we created carboxymethyl hyaluronan (CMHA) with varied degree of modification and investigated the effect on the viscosity of CMHA solutions. Viscosity decreased initially as modification increased, with a minimum viscosity for about 30–40% modification. This was followed by an increase in viscosity around 45–50% modification. The pH of the solution had a variable effect on viscosity, depending on the degree of carboxymethyl modification and buffer. The presence of phosphates in the buffer led to decreased viscosity. We also compared large-scale production lots of CMHA to lab-scale and found that large-scale required extended reaction times to achieve the same degree of modification. Finally, thiolated CMHA was disulfide crosslinked to create hydrogels with increased viscosity and shear-thinning aspects compared to CMHA solutions. PMID:27611817

Pseudouridine and N6-methyladenosine modifications weaken PUF protein/RNA interactions

PubMed Central

AlSadhan, Ishraq; Merriman, Dawn K.; Al-Hashimi, Hashim M.; Herschlag, Daniel

2017-01-01

RNA modifications are ubiquitous in biology, with over 100 distinct modifications. While the vast majority were identified and characterized on abundant noncoding RNA such as tRNA and rRNA, the advent of sensitive sequencing-based approaches has led to the discovery of extensive and regulated modification of eukaryotic messenger RNAs as well. The two most abundant mRNA modifications—pseudouridine (Ψ) and N6-methyladenosine (m6A)—affect diverse cellular processes including mRNA splicing, localization, translation, and decay and modulate RNA structure. Here, we test the hypothesis that RNA modifications directly affect interactions between RNA-binding proteins and target RNA. We show that Ψ and m6A weaken the binding of the human single-stranded RNA binding protein Pumilio 2 (hPUM2) to its consensus motif, with individual modifications having effects up to approximately threefold and multiple modifications giving larger effects. While there are likely to be some cases where RNA modifications essentially fully ablate protein binding, here we see modest responses that may be more common. Such modest effects could nevertheless profoundly alter the complex landscape of RNA:protein interactions, and the quantitative rather than qualitative nature of these effects underscores the need for quantitative, systems-level accounting of RNA:protein interactions to understand post-transcriptional regulation. PMID:28138061

Refining adverse drug reaction signals by incorporating interaction variables identified using emergent pattern mining.

PubMed

Reps, Jenna M; Aickelin, Uwe; Hubbard, Richard B

2016-02-01

To develop a framework for identifying and incorporating candidate confounding interaction terms into a regularised cox regression analysis to refine adverse drug reaction signals obtained via longitudinal observational data. We considered six drug families that are commonly associated with myocardial infarction in observational healthcare data, but where the causal relationship ground truth is known (adverse drug reaction or not). We applied emergent pattern mining to find itemsets of drugs and medical events that are associated with the development of myocardial infarction. These are the candidate confounding interaction terms. We then implemented a cohort study design using regularised cox regression that incorporated and accounted for the candidate confounding interaction terms. The methodology was able to account for signals generated due to confounding and a cox regression with elastic net regularisation correctly ranking the drug families known to be true adverse drug reactions above those that are not. This was not the case without the inclusion of the candidate confounding interaction terms, where confounding leads to a non-adverse drug reaction being ranked highest. The methodology is efficient, can identify high-order confounding interactions and does not require expert input to specify outcome specific confounders, so it can be applied for any outcome of interest to quickly refine its signals. The proposed method shows excellent potential to overcome some forms of confounding and therefore reduce the false positive rate for signal analysis using longitudinal data. Copyright © 2015 Elsevier Ltd. All rights reserved.

Evaluation of Alternative Difference-in-Differences Methods

ERIC Educational Resources Information Center

Yu, Bing

2013-01-01

Difference-in-differences (DID) strategies are particularly useful for evaluating policy effects in natural experiments in which, for example, a policy affects some schools and students but not others. However, the standard DID method may produce biased estimation of the policy effect if the confounding effect of concurrent events varies by…

Confounder Detection in High-Dimensional Linear Models Using First Moments of Spectral Measures.

PubMed

Liu, Furui; Chan, Laiwan

2018-06-12

In this letter, we study the confounder detection problem in the linear model, where the target variable [Formula: see text] is predicted using its [Formula: see text] potential causes [Formula: see text]. Based on an assumption of a rotation-invariant generating process of the model, recent study shows that the spectral measure induced by the regression coefficient vector with respect to the covariance matrix of [Formula: see text] is close to a uniform measure in purely causal cases, but it differs from a uniform measure characteristically in the presence of a scalar confounder. Analyzing spectral measure patterns could help to detect confounding. In this letter, we propose to use the first moment of the spectral measure for confounder detection. We calculate the first moment of the regression vector-induced spectral measure and compare it with the first moment of a uniform spectral measure, both defined with respect to the covariance matrix of [Formula: see text]. The two moments coincide in nonconfounding cases and differ from each other in the presence of confounding. This statistical causal-confounding asymmetry can be used for confounder detection. Without the need to analyze the spectral measure pattern, our method avoids the difficulty of metric choice and multiple parameter optimization. Experiments on synthetic and real data show the performance of this method.

Intuitive Logic Revisited: New Data and a Bayesian Mixed Model Meta-Analysis

PubMed Central

Singmann, Henrik; Klauer, Karl Christoph; Kellen, David

2014-01-01

Recent research on syllogistic reasoning suggests that the logical status (valid vs. invalid) of even difficult syllogisms can be intuitively detected via differences in conceptual fluency between logically valid and invalid syllogisms when participants are asked to rate how much they like a conclusion following from a syllogism (Morsanyi & Handley, 2012). These claims of an intuitive logic are at odds with most theories on syllogistic reasoning which posit that detecting the logical status of difficult syllogisms requires effortful and deliberate cognitive processes. We present new data replicating the effects reported by Morsanyi and Handley, but show that this effect is eliminated when controlling for a possible confound in terms of conclusion content. Additionally, we reanalyze three studies () without this confound with a Bayesian mixed model meta-analysis (i.e., controlling for participant and item effects) which provides evidence for the null-hypothesis and against Morsanyi and Handley's claim. PMID:24755777

Peer influence as a potential magnifier of ADHD diagnosis.

PubMed

Aronson, Brian

2016-11-01

The prevalence of Attention Deficit and Hyperactivity Disorder (ADHD) is growing in America, but its cause is unclear. Scholars have identified many environmental factors that can cause or confound ADHD diagnosis, but epidemiological studies that try to control for confounding factors still find evidence that rates of ADHD diagnosis are increasing. As a preliminary explanation to ADHD's increasing prevalence, this article examines whether core ADHD diagnostic traits are subject to peer influence. If ADHD diagnosis can be confounded by peer influence, there are several mechanisms that could have caused increased rates of diagnosis. With data drawn from two schools across three waves in the National Longitudinal Survey of Adolescent Health (n = 2193), the author uses a stochastic actor oriented model to estimate the effect of peer influence on inattention, controlling for alternative network and behavioral causes. Results indicate that respondents have a strong likelihood to modify their self-reports of inattention, a core ADHD trait, to resemble that of their friends. Copyright © 2016 Elsevier Ltd. All rights reserved.

Desire thinking as a confounder in the relationship between mindfulness and craving: Evidence from a cross-cultural validation of the Desire Thinking Questionnaire.

PubMed

Chakroun-Baggioni, Nadia; Corman, Maya; Spada, Marcantonio M; Caselli, Gabriele; Gierski, Fabien

2017-10-01

Desire thinking and mindfulness have been associated with craving. The aim of the present study was to validate the French version of the Desire Thinking Questionnaire (DTQ) and to investigate the relationship between mindfulness, desire thinking and craving among a sample of university students. Four hundred and ninety six university students completed the DTQ and measures of mindfulness, craving and alcohol use. Results from confirmatory factor analyses showed that the two-factor structure proposed in the original DTQ exhibited suitable goodness-of-fit statistics. The DTQ also demonstrated good internal reliability, temporal stability and predictive validity. A set of linear regressions revealed that desire thinking had a confounding effect in the relationship between mindfulness and craving. The confounding role of desire thinking in the relationship between mindfulness and craving suggests that interrupting desire thinking may be a viable clinical option aimed at reducing craving. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of psychosocial work factors on lifestyle changes: a cohort study.

PubMed

Allard, Karin Olofsson; Thomsen, Jane Frølund; Mikkelsen, Sigurd; Rugulies, Reiner; Mors, Ole; Kærgaard, Anette; Kolstad, Henrik A; Kaerlev, Linda; Andersen, Johan Hviid; Hansen, Ase Marie; Bonde, Jens Peter

2011-12-01

To evaluate the effect of the demand-control-support model, the effort-reward imbalance model, and emotional demands on smoking, alcohol consumption, physical activity, and body mass index. This is a 2-year prospective cohort study of 3224 public sector employees. Measures were assessed with questionnaires. Multiple regression analyses were used to predict changes in lifestyle factors. Low reward predicted smoking, low-decision latitude predicted being inactive, and high demands predicted high-alcohol consumption but only for men at follow-up even after controlling for potential confounders. There were no other significant findings in the expected direction except for some of the confounders. We found only limited and inconsistent support for the hypothesis that a poor psychosocial work environment is associated with an adverse lifestyle.

Exchangeability in the case-crossover design

PubMed Central

Mittleman, Murray A; Mostofsky, Elizabeth

2014-01-01

In cohort and case-control studies, confounding that arises as a result of differences in the distribution of determinants of the outcome between exposure groups leading to non-exchangeability are addressed by restriction, matching or with statistical models. In case-only studies, this issue is addressed by comparing each individual with his/herself. Although case-only designs use self-matching and only include individuals who develop the outcome of interest, issues of non-exchangeability are identical to those that arise in traditional case-control and cohort studies. In this review, we describe one type of case-only design, the case-crossover design, and discuss how the concept of exchangeability can be used to understand issues of confounding, carryover effects, period effects and selection bias in case-crossover studies. PMID:24756878

Transcript Isoform Variation Associated with Cytosine Modification in Human Lymphoblastoid Cell Lines.

PubMed

Zhang, Xu; Zhang, Wei

2016-06-01

Cytosine modification on DNA is variable among individuals, which could correlate with gene expression variation. The effect of cytosine modification on interindividual transcript isoform variation (TIV), however, remains unclear. In this study, we assessed the extent of cytosine modification-specific TIV in lymphoblastoid cell lines (LCLs) derived from unrelated individuals of European and African descent. Our study detected cytosine modification-specific TIVs for 17% of the analyzed genes at a 5% false discovery rate. Forty-five percent of the TIV-associated cytosine modifications correlated with the overall gene expression levels as well, with the corresponding CpG sites overrepresented in transcript initiation sites, transcription factor binding sites, and distinct histone modification peaks, suggesting that alternative isoform transcription underlies the TIVs. Our analysis also revealed 33% of the TIV-associated cytosine modifications that affected specific exons, with the corresponding CpG sites overrepresented in exon/intron junctions, splicing branching points, and transcript termination sites, implying that the TIVs are attributable to alternative splicing or transcription termination. Genetic and epigenetic regulation of TIV shared target preference but exerted independent effects on 61% of the common exon targets. Cytosine modification-specific TIVs detected from LCLs were differentially enriched in those detected from various tissues in The Cancer Genome Atlas, indicating their developmental dependency. Genes containing cytosine modification-specific TIVs were enriched in pathways of cancers and metabolic disorders. Our study demonstrated a prominent effect of cytosine modification variation on the transcript isoform spectrum over gross transcript abundance and revealed epigenetic contributions to diseases that were mediated through cytosine modification-specific TIV. Copyright © 2016 by the Genetics Society of America.

Use of Self-Matching to Control for Stable Patient Characteristics While Addressing Time-Varying Confounding on Treatment Effect: A Case Study of Older Intensive Care Patients.

PubMed

Han, Ling; Pisani, M A; Araujo, K L B; Allore, Heather G

Exposure-crossover design offers a non-experimental option to control for stable baseline confounding through self-matching while examining causal effect of an exposure on an acute outcome. This study extends this approach to longitudinal data with repeated measures of exposure and outcome using data from a cohort of 340 older medical patients in an intensive care unit (ICU). The analytic sample included 92 patients who received ≥1 dose of haloperidol, an antipsychotic medication often used for patients with delirium. Exposure-crossover design was implemented by sampling the 3-day time segments prior ( Induction) and posterior ( Subsequent) to each treatment episode of receiving haloperidol. In the full cohort, there was a trend of increasing delirium severity scores (Mean±SD: 4.4±1.7) over the course of the ICU stay. After exposure-crossover sampling, the delirium severity score decreased from the Induction (4.9) to the Subsequent (4.1) intervals, with the treatment episode falling in-between (4.5). Based on a GEE Poisson model accounting for self-matching and within-subject correlation, the unadjusted mean delirium severity scores was -0.55 (95% CI: -1.10, -0.01) points lower for the Subsequent than the Induction intervals. The association diminished by 32% (-0.38, 95%CI: -0.99, 0.24) after adjusting only for ICU confounding, while being slightly increased by 7% (-0.60, 95%CI: -1.15, -0.04) when adjusting only for baseline characteristics. These results suggest that longitudinal exposure-crossover design is feasible and capable of partially removing stable baseline confounding through self-matching. Loss of power due to eliminating treatment-irrelevant person-time and uncertainty around allocating person-time to comparison intervals remain methodological challenges.

Gardening and age-related weight gain: Results from a cross-sectional survey of Denver residents.

PubMed

Litt, Jill S; Lambert, Jeffrey Richard; Glueck, Deborah H

2017-12-01

This study examined whether gardening modifies the association between age and body mass index (BMI). We used data from the Neighborhood Environments and Health Survey, which was conducted in Denver (N = 469) between 2006 and 2007. We fit two general linear mixed models. The base model had BMI in kg/m 2 as the outcome, and age, an indicator variable for non-gardening status and the age-by-non-gardening status interaction as predictors. The adjusted model included as covariates the potential confounders of education, ethnicity and self-reported health. We assessed self-selection bias and confounding. BMI was 27.18 kg/m 2 for non-gardeners, 25.62 kg/m 2 for home gardeners, and 24.17 kg/m 2 for community gardeners. In the base model, a statistically significant association was observed between age and BMI for non-gardeners but not for the combined community and home gardening group (F = 9.27, ndf = 1, ddf = 441, p = 0.0025). In the adjusted model, the association between age and BMI in non-gardeners was not statistically significant (F = 1.72, ndf = 1, ddf = 431, p = 0.1908). Gardeners differed on social and demographic factors when compared to non-gardeners. The results from the base model are consistent with the hypothesis that gardening might offset age-related weight gain. However, the cross-sectional design does not permit differentiation of true causal effects from the possible effects of bias and confounding. As a follow-up study, to remove bias and confounding, we are conducting a randomized clinical trial of community gardening in Denver.

Normality of upper and lower peripheral pulse transit time of normotensive and hypertensive children.

PubMed

Foo, Jong Yong Abdiel

2007-08-01

The ankle-brachial index (ABI) is known to be indicative of sub-clinical peripheral arterial diseases that are correlated with cardiovascular disease risk factors like atherosclerosis or ischemic extremity. Due to its occluding measurement nature, this may not be appealing to less cooperative patients when multiple prolonged screening is required. A simple and non-intrusive approach termed pulse transit time ratio (PTTR) has recently shown to be potential surrogate marker for the prolonged ABI measurement. Other studies have also suggested that subjects with hypertension have stiffer arterial wall and thereby can confound transit time related parameters. Thus, it becomes important to understand the PTTR normality and difference of hypertensive children when compared to those measured from normotensive children. About 55 normotensive (39 male; aged 8.4 +/- 2.3 yr) and 4 hypertensive (4 male; aged 5-10 yr) Caucasian children were recruited from the same geographical location. A customized device was used to compute pulse transit time related measurements. Since the PTTR approach produced a delta value that was similar to that of ABI, possible inter-subject physiologic differences had limited confounding effects on the derived PTTR parameter. The obtained transit time measurements from the hypertensive children had lower pulse transit time value when compared to their normotensive counterparts. However, the statistical analysis indicated that they had insignificant PTTR difference (p > 0.01) from those seen in the normotensive children. The findings herein suggest that stiffer arterial wall may have confounding effects on the derived transit time related measurements but it is limited on the PTTR parameter. Similar to the ABI approach, PTTR may be only confounded by abnormal local changes in either of the measured peripheral arterial wall. Hence, the PTTR technique shows promise to be an ABI marker from this perspective.

Methodological comparison of marginal structural model, time-varying Cox regression, and propensity score methods: the example of antidepressant use and the risk of hip fracture.

PubMed

Ali, M Sanni; Groenwold, Rolf H H; Belitser, Svetlana V; Souverein, Patrick C; Martín, Elisa; Gatto, Nicolle M; Huerta, Consuelo; Gardarsdottir, Helga; Roes, Kit C B; Hoes, Arno W; de Boer, Antonius; Klungel, Olaf H

2016-03-01

Observational studies including time-varying treatments are prone to confounding. We compared time-varying Cox regression analysis, propensity score (PS) methods, and marginal structural models (MSMs) in a study of antidepressant [selective serotonin reuptake inhibitors (SSRIs)] use and the risk of hip fracture. A cohort of patients with a first prescription for antidepressants (SSRI or tricyclic antidepressants) was extracted from the Dutch Mondriaan and Spanish Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP) general practice databases for the period 2001-2009. The net (total) effect of SSRI versus no SSRI on the risk of hip fracture was estimated using time-varying Cox regression, stratification and covariate adjustment using the PS, and MSM. In MSM, censoring was accounted for by inverse probability of censoring weights. The crude hazard ratio (HR) of SSRI use versus no SSRI use on hip fracture was 1.75 (95%CI: 1.12, 2.72) in Mondriaan and 2.09 (1.89, 2.32) in BIFAP. After confounding adjustment using time-varying Cox regression, stratification, and covariate adjustment using the PS, HRs increased in Mondriaan [2.59 (1.63, 4.12), 2.64 (1.63, 4.25), and 2.82 (1.63, 4.25), respectively] and decreased in BIFAP [1.56 (1.40, 1.73), 1.54 (1.39, 1.71), and 1.61 (1.45, 1.78), respectively]. MSMs with stabilized weights yielded HR 2.15 (1.30, 3.55) in Mondriaan and 1.63 (1.28, 2.07) in BIFAP when accounting for censoring and 2.13 (1.32, 3.45) in Mondriaan and 1.66 (1.30, 2.12) in BIFAP without accounting for censoring. In this empirical study, differences between the different methods to control for time-dependent confounding were small. The observed differences in treatment effect estimates between the databases are likely attributable to different confounding information in the datasets, illustrating that adequate information on (time-varying) confounding is crucial to prevent bias. Copyright © 2016 John Wiley & Sons, Ltd.

Brief Communication: Latent toxoplasmosis and salivary testosterone concentration--important confounding factors in second to fourth digit ratio studies.

PubMed

Flegr, Jaroslav; Lindová, Jitka; Pivoñková, Vera; Havlícek, Jan

2008-12-01

A sexually dimorphic characteristic, the second to fourth digit ratio (2D:4D ratio), has been shown to reflect the prenatal concentration of sex steroid hormones and to correlate with many personality, physiological, and life history traits. The correlations are usually stronger for the right than the left hand. Most studies have shown that the 2D:4D ratio does not vary with age or postnatal concentration of sex steroid hormones. Recently, a strong association between left hand 2D:4D ratio and infection with a common human parasite Toxoplasma has been reported. We hypothesized that the confounding effect of Toxoplasma infection on left hand 2D:4D ratio could be responsible for the stronger association between different traits and right hand rather than left hand 2D:4D ratio. This confounding effect of toxoplasmosis could also be responsible for the difficulty in finding an association between 2D:4D ratio and age or postnatal steroid hormone concentration. To test this hypothesis, we analyzed the association between sex and age and 2D:4D ratio in a population of 194 female and 106 male students with and without controlling for the confounding variables of Toxoplasma infection and testosterone concentration. Our results showed that the relationship between age and sex and 2D:4D ratio increased sharply when Toxoplasma infection and testosterone concentration were controlled. These results suggest that left hand 2D:4D ratio is more susceptible to postnatal influences and that the confounding factors of Toxoplasma infection, testosterone concentration and possibly also age, should be controlled in future 2D:4D ratio studies. Because of a stronger 2D:4D dimorphism in Toxoplasma-infected than Toxoplasma-free subjects, we predict that 2D:4D ratio dimorphism as well as right hand/left hand 2D:4D ratio dimorphism will be higher in countries with a high prevalence of Toxoplasma infection than in those with a low prevalence. (c) 2008 Wiley-Liss, Inc.

Economic Effects of Precipitation Enhancement in the Corn Belt.

NASA Astrophysics Data System (ADS)

Gapcia, Philip; Changnon, Stanley; Pinar, Musa

1990-01-01

Policy formulation in weather modification requires an understanding of the economic effects from altered weather. The focus of this study is to provide insight into the beneficiaries of a functioning weather modification technology when applied at various spatial and temporal levels. An econometric model which links the corn/scybean production to U.S. cattle, hog and poultry sectors is used to determine the effects of precipitation enhancement in the U.S. Corn Belt, a humid climatic region. A regional supply formulation permits assessment of weather modification on production, prices, revenues to producers, and savings in consumers expenditures on meat. The results provide insight into the distribution of economic effects, emphasize the importance of careful planning in the use of weather modification technology, and provide useful information on the roles of local, state, and federal governments in the support of weather modification.

Functional Anatomy of Recognition of Chinese Multi-Character Words: Convergent Evidence from Effects of Transposable Nonwords, Lexicality, and Word Frequency.

PubMed

Lin, Nan; Yu, Xi; Zhao, Ying; Zhang, Mingxia

2016-01-01

This fMRI study aimed to identify the neural mechanisms underlying the recognition of Chinese multi-character words by partialling out the confounding effect of reaction time (RT). For this purpose, a special type of nonword-transposable nonword-was created by reversing the character orders of real words. These nonwords were included in a lexical decision task along with regular (non-transposable) nonwords and real words. Through conjunction analysis on the contrasts of transposable nonwords versus regular nonwords and words versus regular nonwords, the confounding effect of RT was eliminated, and the regions involved in word recognition were reliably identified. The word-frequency effect was also examined in emerged regions to further assess their functional roles in word processing. Results showed significant conjunctional effect and positive word-frequency effect in the bilateral inferior parietal lobules and posterior cingulate cortex, whereas only conjunctional effect was found in the anterior cingulate cortex. The roles of these brain regions in recognition of Chinese multi-character words were discussed.

Functional Anatomy of Recognition of Chinese Multi-Character Words: Convergent Evidence from Effects of Transposable Nonwords, Lexicality, and Word Frequency

PubMed Central

Lin, Nan; Yu, Xi; Zhao, Ying; Zhang, Mingxia

2016-01-01

This fMRI study aimed to identify the neural mechanisms underlying the recognition of Chinese multi-character words by partialling out the confounding effect of reaction time (RT). For this purpose, a special type of nonword—transposable nonword—was created by reversing the character orders of real words. These nonwords were included in a lexical decision task along with regular (non-transposable) nonwords and real words. Through conjunction analysis on the contrasts of transposable nonwords versus regular nonwords and words versus regular nonwords, the confounding effect of RT was eliminated, and the regions involved in word recognition were reliably identified. The word-frequency effect was also examined in emerged regions to further assess their functional roles in word processing. Results showed significant conjunctional effect and positive word-frequency effect in the bilateral inferior parietal lobules and posterior cingulate cortex, whereas only conjunctional effect was found in the anterior cingulate cortex. The roles of these brain regions in recognition of Chinese multi-character words were discussed. PMID:26901644

Task-independent effects are potential confounders in longitudinal imaging studies of learning in schizophrenia

PubMed Central

Korostil, Michele; Fatima, Zainab; Kovacevic, Natasha; Menon, Mahesh; McIntosh, Anthony Randal

2015-01-01

Learning impairment is a core deficit in schizophrenia that impacts on real-world functioning and yet, elucidating its underlying neural basis remains a challenge. A key issue when interpreting learning-task experiments is that task-independent changes may confound interpretation of task-related signal changes in neuroimaging studies. The nature of these task-independent changes in schizophrenia is unknown. Therefore, we examined task-independent “time effects” in a group of participants with schizophrenia contrasted with healthy participants in a longitudinal fMRI learning-experiment designed to allow for examination of non-specific effects of time. Flanking the learning portions of the experiment with a task-of-no-interest allowed us to extract task-independent BOLD changes. Task-independent effects occurred in both groups, but were more robust in the schizophrenia group. There was a significant interaction effect between group and time in a distributed activity pattern that included inferior and superior temporal regions, frontal areas (left anterior insula and superior medial gyri), and parietal areas (posterior cingulate cortices and precuneus). This pattern showed task-independent linear decrease in BOLD amplitude over the two scanning sessions for the schizophrenia group, but showed either opposite effect or no activity changes for the control group. There was a trend towards a correlation between task-independent effects and the presence of more negative symptoms in the schizophrenia group. The strong interaction between group and time suggests that both the scanning experience as a whole and the transition between task-types evokes a different response in persons with schizophrenia and may confound interpretation of learning-related longitudinal imaging experiments if not explicitly considered. PMID:26759790

Wind turbines and idiopathic symptoms: The confounding effect of concurrent environmental exposures.

PubMed

Blanes-Vidal, Victoria; Schwartz, Joel

2016-01-01

Whether or not wind turbines pose a risk to human health is a matter of heated debate. Personal reactions to other environmental exposures occurring in the same settings as wind turbines may be responsible of the reported symptoms. However, these have not been accounted for in previous studies. We investigated whether there is an association between residential proximity to wind turbines and idiopathic symptoms, after controlling for personal reactions to other environmental co-exposures. We assessed wind turbine exposures in 454 residences as the distance to the closest wind turbine (Dw) and number of wind turbines <1000m (Nw1000). Information on symptoms, demographics and personal reactions to exposures was obtained by a blind questionnaire. We identified confounders using confounders' selection criteria and used adjusted logistic regression models to estimate associations. When controlling only for socio-demographic characteristics, log10Dw was associated with "unnatural fatigue" (ORadj=0.38, 95%CI=0.15-1.00) and "difficulty concentrating" (ORadj=0.26, 95%CI=0.08-0.83) and Nw1000 was associated with "unnatural fatigue" (ORadj=1.35, 95%CI=1.07-1.70) and "headache" (ORadj=1.26, 95%CI=1.00-1.58). After controlling for personal reactions to noise from sources different from wind turbines and agricultural odor exposure, we did not observe a significant relationship between residential proximity to wind turbines and symptoms and the parameter estimates were attenuated toward zero. Wind turbines-health associations can be confounded by personal reactions to other environmental co-exposures. Isolated associations reported in the literature may be due to confounding bias. Copyright © 2016 Elsevier Inc. All rights reserved.

The role of sex and body weight on the metabolic effects of high-fat diet in C57BL/6N mice.

PubMed

Ingvorsen, C; Karp, N A; Lelliott, C J

2017-04-10

Metabolic disorders are commonly investigated using knockout and transgenic mouse models on the C57BL/6N genetic background due to its genetic susceptibility to the deleterious metabolic effects of high-fat diet (HFD). There is growing awareness of the need to consider sex in disease progression, but limited attention has been paid to sexual dimorphism in mouse models and its impact in metabolic phenotypes. We assessed the effect of HFD and the impact of sex on metabolic variables in this strain. We generated a reference data set encompassing glucose tolerance, body composition and plasma chemistry data from 586 C57BL/6N mice fed a standard chow and 733 fed a HFD collected as part of a high-throughput phenotyping pipeline. Linear mixed model regression analysis was used in a dual analysis to assess the effect of HFD as an absolute change in phenotype, but also as a relative change accounting for the potential confounding effect of body weight. HFD had a significant impact on all variables tested with an average absolute effect size of 29%. For the majority of variables (78%), the treatment effect was modified by sex and this was dominated by male-specific or a male stronger effect. On average, there was a 13.2% difference in the effect size between the male and female mice for sexually dimorphic variables. HFD led to a significant body weight phenotype (24% increase), which acts as a confounding effect on the other analysed variables. For 79% of the variables, body weight was found to be a significant source of variation, but even after accounting for this confounding effect, similar HFD-induced phenotypic changes were found to when not accounting for weight. HFD and sex are powerful modifiers of metabolic parameters in C57BL/6N mice. We also demonstrate the value of considering body size as a covariate to obtain a richer understanding of metabolic phenotypes.

Three estimates of the association between linear growth failure and cognitive ability.

PubMed

Cheung, Y B; Lam, K F

2009-09-01

To compare three estimators of association between growth stunting as measured by height-for-age Z-score and cognitive ability in children, and to examine the extent statistical adjustment for covariates is useful for removing confounding due to socio-economic status. Three estimators, namely random-effects, within- and between-cluster estimators, for panel data were used to estimate the association in a survey of 1105 pairs of siblings who were assessed for anthropometry and cognition. Furthermore, a 'combined' model was formulated to simultaneously provide the within- and between-cluster estimates. Random-effects and between-cluster estimators showed strong association between linear growth and cognitive ability, even after adjustment for a range of socio-economic variables. In contrast, the within-cluster estimator showed a much more modest association: For every increase of one Z-score in linear growth, cognitive ability increased by about 0.08 standard deviation (P < 0.001). The combined model verified that the between-cluster estimate was significantly larger than the within-cluster estimate (P = 0.004). Residual confounding by socio-economic situations may explain a substantial proportion of the observed association between linear growth and cognition in studies that attempt to control the confounding by means of multivariable regression analysis. The within-cluster estimator provides more convincing and modest results about the strength of association.

Measurement error, time lag, unmeasured confounding: Considerations for longitudinal estimation of the effect of a mediator in randomised clinical trials.

PubMed

Goldsmith, K A; Chalder, T; White, P D; Sharpe, M; Pickles, A

2018-06-01

Clinical trials are expensive and time-consuming and so should also be used to study how treatments work, allowing for the evaluation of theoretical treatment models and refinement and improvement of treatments. These treatment processes can be studied using mediation analysis. Randomised treatment makes some of the assumptions of mediation models plausible, but the mediator-outcome relationship could remain subject to bias. In addition, mediation is assumed to be a temporally ordered longitudinal process, but estimation in most mediation studies to date has been cross-sectional and unable to explore this assumption. This study used longitudinal structural equation modelling of mediator and outcome measurements from the PACE trial of rehabilitative treatments for chronic fatigue syndrome (ISRCTN 54285094) to address these issues. In particular, autoregressive and simplex models were used to study measurement error in the mediator, different time lags in the mediator-outcome relationship, unmeasured confounding of the mediator and outcome, and the assumption of a constant mediator-outcome relationship over time. Results showed that allowing for measurement error and unmeasured confounding were important. Contemporaneous rather than lagged mediator-outcome effects were more consistent with the data, possibly due to the wide spacing of measurements. Assuming a constant mediator-outcome relationship over time increased precision.

Measurement error, time lag, unmeasured confounding: Considerations for longitudinal estimation of the effect of a mediator in randomised clinical trials

PubMed Central

Goldsmith, KA; Chalder, T; White, PD; Sharpe, M; Pickles, A

2016-01-01

Clinical trials are expensive and time-consuming and so should also be used to study how treatments work, allowing for the evaluation of theoretical treatment models and refinement and improvement of treatments. These treatment processes can be studied using mediation analysis. Randomised treatment makes some of the assumptions of mediation models plausible, but the mediator–outcome relationship could remain subject to bias. In addition, mediation is assumed to be a temporally ordered longitudinal process, but estimation in most mediation studies to date has been cross-sectional and unable to explore this assumption. This study used longitudinal structural equation modelling of mediator and outcome measurements from the PACE trial of rehabilitative treatments for chronic fatigue syndrome (ISRCTN 54285094) to address these issues. In particular, autoregressive and simplex models were used to study measurement error in the mediator, different time lags in the mediator–outcome relationship, unmeasured confounding of the mediator and outcome, and the assumption of a constant mediator–outcome relationship over time. Results showed that allowing for measurement error and unmeasured confounding were important. Contemporaneous rather than lagged mediator–outcome effects were more consistent with the data, possibly due to the wide spacing of measurements. Assuming a constant mediator–outcome relationship over time increased precision. PMID:27647810

On the Etiology of Sexual Dysfunction

ERIC Educational Resources Information Center

Apfelbaum, Bernard

1977-01-01

Lack of consideration of the sexually functional population has led to misconceptions about causes of sexual dysfunction functioning. Automatic functioning can mask effects of pathogenic influences on sexuality, making these effects appear random, confounding etiological issues and creating the belief that causes of sexual dysfunction and disorder…

Instrumental variable methods in comparative safety and effectiveness research†

PubMed Central

Brookhart, M. Alan; Rassen, Jeremy A.; Schneeweiss, Sebastian

2010-01-01

Summary Instrumental variable (IV) methods have been proposed as a potential approach to the common problem of uncontrolled confounding in comparative studies of medical interventions, but IV methods are unfamiliar to many researchers. The goal of this article is to provide a non-technical, practical introduction to IV methods for comparative safety and effectiveness research. We outline the principles and basic assumptions necessary for valid IV estimation, discuss how to interpret the results of an IV study, provide a review of instruments that have been used in comparative effectiveness research, and suggest some minimal reporting standards for an IV analysis. Finally, we offer our perspective of the role of IV estimation vis-à-vis more traditional approaches based on statistical modeling of the exposure or outcome. We anticipate that IV methods will be often underpowered for drug safety studies of very rare outcomes, but may be potentially useful in studies of intended effects where uncontrolled confounding may be substantial. PMID:20354968

The intention interference effect.

PubMed

Cohen, Anna-Lisa; Kantner, Justin; Dixon, Roger A; Lindsay, D Stephen

2011-01-01

Intentions have been shown to be more accessible (e.g., more quickly and accurately recalled) compared to other sorts of to-be-remembered information; a result termed an intention superiority effect (Goschke & Kuhl, 1993). In the current study, we demonstrate an intention interference effect (IIE) in which color-naming performance in a Stroop task was slower for words belonging to an intention that participants had to remember to carry out (Do-the-Task condition) versus an intention that did not have to be executed (Ignore-the-Task condition). In previous work (e.g., Cohen et al., 2005), having a prospective intention in mind was confounded with carrying a memory load. In Experiment 1, we added a digit-retention task to control for effects of cognitive load. In Experiment 2, we eliminated the memory confound in a new way, by comparing intention-related and control words within each trial. Results from both Experiments 1 and 2 revealed an IIE suggesting that interference is very specific to the intention, not just to a memory load.

Effect of site-specific modification on restriction endonucleases and DNA modification methyltransferases.

PubMed Central

McClelland, M; Nelson, M; Raschke, E

1994-01-01

Restriction endonucleases have site-specific interactions with DNA that can often be inhibited by site-specific DNA methylation and other site-specific DNA modifications. However, such inhibition cannot generally be predicted. The empirically acquired data on these effects are tabulated for over 320 restriction endonucleases. In addition, a table of known site-specific DNA modification methyltransferases and their specificities is presented along with EMBL database accession numbers for cloned genes. PMID:7937074

Microscopic mechanism of amino silicone oil modification and modification effect with different amino group contents based on molecular dynamics simulation

NASA Astrophysics Data System (ADS)

He, Liping; Li, Wenjun; Chen, Dachuan; Yuan, Jianmin; Lu, Gang; Zhou, Dianwu

2018-05-01

The microscopic mechanism of amino silicone oil (ASO) modification of natural fiber was investigated for the first time using molecular dynamics (MD) simulation at the atomic and molecular levels. The MD simulation results indicated that the ASO molecular interacted with the cellulose molecular within the natural fiber, mainly by intermolecular forces of Nsbnd Hsbnd O and Osbnd Hsbnd N hydrogen bonds and the molecular chain of ASO absorbed onto the natural fiber in a selective orientation, i.e., the hydrophobic alkyl groups (sbnd CnH2n+1) project outward and the polar amino groups (sbnd NH2) point to the surface of natural fiber. Consequently, the ASO modification changed the surface characteristic of natural fiber from hydrophilic to hydrophobic. Furthermore, the modification effects of the ASO modification layer with different amino group contents (m:n ratio) were also evaluated in this study by calculating the binding energy between the ASO modifier and natural fiber, and the cohesive energy density and free volume of the ASO modification layer. The results showed that the binding energy reached a maximum when the m:n ratio of ASO was of 8:4, suggesting that a good bonding strength was achieved at this m:n ratio. It was also found that the cohesive energy density enhanced with the increase in the amino group content, and the higher the cohesive energy density, the easier the formation of the ASO modification layer. However, the fraction free volume decreased with the increase in the amino group content. This is good for improving the water-proof property of natural fiber. The present work can provide an effective method for predicting the modification effects and designing the optimized m:n ratio of ASO modification.

Are bioequivalence studies of levothyroxine sodium formulations in euthyroid volunteers reliable?

PubMed

Blakesley, Vicky; Awni, Walid; Locke, Charles; Ludden, Thomas; Granneman, G Richard; Braverman, Lewis E

2004-03-01

Levothyroxine (LT4) has a narrow therapeutic index. Consequently, precise standards for assessing the bioequivalence of different LT4 products are vital. We examined the methodology that the Food and Drug Administration (FDA) recommends for comparing the bioavailability of LT4 products, as well as three modifications to correct for endogenous, thyroxine (T4) levels, to determine if the methodology could distinguish LT4 products that differ by 12.5%, 25%, or 33%. With no baseline correction for the endogenous T4 pool, differences in administered LT4 doses that differed by 25%-33% could not be detected (450 microg and 400 microg doses versus 600 microg dose, respectively). The three mathematical correction methods could distinguish the doses that differed by 25% and 33%. None of the correction methods could distinguish dosage strengths that differed by 12.5% (450 microg versus 400 microg). Dose differences within this range are known to result in clinically relevant differences in safety and effectiveness. Methods of analysis of bioequivalence data that do not consider endogenous T4 concentrations confound accurate quantitation and interpretation of LT4 bioavailability. As a result, products inappropriately deemed bioequivalent may put patients at risk for iatrogenic hyperthyroidism or hypothyroidism. More precise methods for defining bioequivalence are required in order to ensure that LT4 products accepted as bioequivalent will perform equivalently in patients without the need for further monitoring and retitration of their dose.

Associations Between Dietary Patterns and Head and Neck Cancer

PubMed Central

Bradshaw, Patrick T.; Siega-Riz, Anna Maria; Campbell, Marci; Weissler, Mark C.; Funkhouser, William K.; Olshan, Andrew F.

2012-01-01

Few studies have examined the associations between dietary patterns and head and neck squamous cell carcinoma (SCC) or whether they differ by race. This was evaluated using data from a population-based case-control study (2002–2006) including 1,176 cases of head and neck SCC and 1,317 age-, race-, and gender-matched controls from central and eastern North Carolina whose diets had been assessed by food frequency questionnaire. Factor analysis identified 2 patterns of intake: 1) high consumption of fruits, vegetables, and lean protein and 2) high consumption of fried foods, high-fat and processed meats, and sweets. Associations were estimated using logistic regression, adjusting for matching factors and confounders. Heterogeneity by tumor site (oral/pharyngeal vs. laryngeal) and effect-measure modification were also evaluated. Reduced odds of head and neck SCC were found for the fruit, vegetable, and lean protein pattern (for highest quartile vs. lowest, odds ratio = 0.53, 95% confidence interval: 0.39, 0.71). The fried foods, high-fat and processed meats, and sweets pattern was positively associated only with laryngeal cancer (odds ratio = 2.12, 95% confidence interval: 1.21, 3.72). These findings underline the importance of a dietary pattern rich in fruits and vegetables and low in high-fat and processed meats and sweets for prevention of head and neck cancer. PMID:22575416

Oral health and cognitive function in the Third National Health and Nutrition Examination Survey (NHANES III).

PubMed

Stewart, Robert; Sabbah, Wael; Tsakos, Georgios; D'Aiuto, Francesco; Watt, Richard G

2008-10-01

To investigate the association between oral health and cognitive function in early-, mid-, and late-adult life. A secondary analysis was carried out of a large, well-characterized community sample (NHANES III). Analyzed variables included three measures of oral health (gingival bleeding, loss of periodontal attachment, loss of teeth) and three measures of cognitive function: the Symbol Digit Substitution Test (SDST), the Serial Digit Learning Test (SDLT) (both in 5138 participants aged 20-59 years), and a Story Recall test (in 1555 participants aged >or=70 years). Other covariates in linear regression models included age, gender, ethnicity, education and poverty, and cardiovascular risk factors. Worse scores on all three measures of oral health status were significantly associated with poorer performance on all three measures of cognitive function after adjustment for age. Education was an important confounding factor. However, after full adjustment for all other covariates, gingival bleeding (%) and loss of periodontal attachment (%) remained associated with relative impairment on SDST score (B coefficients both = 0.003), and gingival bleeding was associated with relative impairment on SDLT (B = 0.017). No effect modification by age was observed. Poor oral health is associated with worse cognitive function throughout adult life. This may, in part, be accounted for by early life education and social status. However, the possibility of direct causal pathways requires further investigation.

The confounding effects of hybridization on phylogenetic estimation in the New Zealand cicada genus Kikihia.

PubMed

Banker, Sarah E; Wade, Elizabeth J; Simon, Chris

2017-11-01

Phylogenetic studies of multiple independently inherited nuclear genes considered in combination with patterns of inheritance of organelle DNA have provided considerable insight into the history of species evolution. In particular, investigations of cicadas in the New Zealand genus Kikihia have identified interesting cases where mitochondrial DNA (mtDNA) crosses species boundaries in some species pairs but not others. Previous phylogenetic studies focusing on mtDNA largely corroborated Kikihia species groups identified by song, morphology and ecology with the exception of a unique South Island mitochondrial haplotype clade-the Westlandica group. This newly identified group consists of diverse taxa previously classified as belonging to three different sub-generic clades. We sequenced five nuclear loci from multiple individuals from every species of Kikihia to assess the nuclear gene concordance for this newly-identified mtDNA lineage. Bayes Factor analysis of the constrained phylogeny suggests some support for the mtDNA-based hypotheses, despite the fact that neither concatenation nor multiple species tree methods resolve the Westlandica group as monophyletic. The nuclear analyses suggest a geographic distinction between clearly defined monophyletic North Island clades and unresolved South Island clades. We suggest that more extreme habitat modification on South Island during the Pliocene and Pleistocene resulted in secondary contact and hybridization between species pairs and a series of mitochondrial capture events followed by subsequent lineage evolution. Copyright © 2017 Elsevier Inc. All rights reserved.

Marital status and optimism score among breast cancer survivors.

PubMed

Croft, Lindsay; Sorkin, John; Gallicchio, Lisa

2014-11-01

There are an increasing number of breast cancer survivors, but their psychosocial and supportive care needs are not well-understood. Recent work has found marital status, social support, and optimism to be associated with quality of life, but little research has been conducted to understand how these factors relate to one another. Survey data from 722 breast cancer survivors were analyzed to estimate the association between marital status and optimism score, as measured using the Life Orientation Test-Revised. Linear regression was used to estimate the relationship of marital status and optimism, controlling for potential confounding variables and assessing effect modification. The results showed that the association between marital status and optimism was modified by time since breast cancer diagnosis. Specifically, in those most recently diagnosed (within 5 years), married breast cancer survivors had a 1.50 higher mean optimism score than unmarried survivors (95 % confidence interval (CI) 0.37, 2.62; p = 0.009). The difference in optimism score by marital status was not present more than 5 years from breast cancer diagnosis. Findings suggest that among breast cancer survivors within 5 years since diagnosis, those who are married have higher optimism scores than their unmarried counterparts; this association was not observed among longer-term breast cancer survivors. Future research should examine whether the difference in optimism score among this subgroup of breast cancer survivors is clinically relevant.

Atraumatic perspectives of ART: psychological and physiological aspects of treatment with and without rotary instruments.

PubMed

Schriks, M C M; van Amerongen, W E

2003-02-01

Atraumatic Restorative Treatment, ART, is a method of minimal caries intervention that uses only hand instruments. The aim of the present study was to explore a possible difference between the extent of discomfort experienced during dental treatment according to the ART approach and a method using rotary instruments. The study was performed in Indonesia. A total of 403 children were randomly divided in two groups. In each child, one class II restoration in a deciduous molar was made. One group received treatment using rotary instruments (750 r.p.m.). The other group was treated according to the ART approach. Glass ionomer cement was used for restoration in both groups. Discomfort scores were determined using both physiological measurements (heart rate) and behavioral observations (Venham) on specific moments during the treatment. Venham scores showed a marked difference between the two groups at most time points. Heart rate measurements were different at deep excavation. Also, a clear relation between Venham scores and heart rate measurements could be found at all time points. Confounding could be shown for operating dentist, gender of the patient and initial anxiety, not for age. No effect modification could be shown. It can be concluded that children treated according to the ART approach using hand instruments alone experience less discomfort than those treated using rotary instruments.

Tea Consumption Reduces the Incidence of Neurocognitive Disorders: Findings from the Singapore Longitudinal Aging Study.

PubMed

Feng, L; Chong, M-S; Lim, W-S; Gao, Q; Nyunt, M S; Lee, T-S; Collinson, S L; Tsoi, T; Kua, E-H; Ng, T-P

2016-01-01

To examine the relationships between tea consumption habits and incident neurocognitive disorders (NCD) and explore potential effect modification by gender and the apolipoprotein E (APOE) genotype. Population-based longitudinal study. The Singapore Longitudinal Aging Study (SLAS). 957 community-living Chinese elderly who were cognitively intact at baseline. We collected tea consumption information at baseline from 2003 to 2005 and ascertained incident cases of neurocognitive disorders (NCD) from 2006 to 2010. Odds ratio (OR) of association were calculated in logistic regression models that adjusted for potential confounders. A total of 72 incident NCD cases were identified from the cohort. Tea intake was associated with lower risk of incident NCD, independent of other risk factors. Reduced NCD risk was observed for both green tea (OR=0.43) and black/oolong tea (OR=0.53) and appeared to be influenced by the changing of tea consumption habit at follow-up. Using consistent non-tea consumers as the reference, only consistent tea consumers had reduced risk of NCD (OR=0.39). Stratified analyses indicated that tea consumption was associated with reduced risk of NCD among females (OR=0.32) and APOE ε4 carriers (OR=0.14) but not males and non APOE ε4 carriers. Regular tea consumption was associated with lower risk of neurocognitive disorders among Chinese elderly. Gender and genetic factors could possibly modulate this association.

Flaws in Flynn Effect Research with the Wechsler Scales

ERIC Educational Resources Information Center

Weiss, Lawrence G.; Gregoire, Jacques; Zhu, Jianjun

2016-01-01

Many Flynn effect (FE) studies compare scores across different editions of Wechsler's IQ tests. When construct changes are introduced by the test developers in the new edition, however, the presumed generational effects are difficult to untangle from changes due to test content. To remove this confound, we use the same edition of Wechsler…

Lifestyle modification in the management of the metabolic syndrome: achievements and challenges

PubMed Central

Grave, Riccardo Dalle; Calugi, Simona; Centis, Elena; Marzocchi, Rebecca; Ghoch, Marwan El; Marchesini, Giulio

2010-01-01

Lifestyle modification based on behavior therapy is the most important and effective strategy to manage the metabolic syndrome. Modern lifestyle modification therapy combines specific recommendations on diet and exercise with behavioral and cognitive strategies. The intervention may be delivered face-to-face or in groups, or in groups combined with individual sessions. The main challenge of treatment is helping patients maintain healthy behavior changes in the long term. In the last few years, several strategies have been evaluated to improve the long-term effect of lifestyle modification. Promising results have been achieved by combining lifestyle modification with pharmacotherapy, using meals replacement, setting higher physical activity goals, and long-term care. The key role of cognitive processes in the success/failure of weight loss and maintenance suggests that new cognitive procedures and strategies should be included in the traditional lifestyle modification interventions, in order to help patients build a mind-set favoring long-term lifestyle changes. These new strategies raise optimistic expectations for an effective treatment of metabolic syndrome with lifestyle modifications, provided public health programs to change the environment where patients live support them. PMID:21437107

Prediction of effects of wing contour modifications on low-speed maximum lift and transonic performance for the EA-6B aircraft

NASA Technical Reports Server (NTRS)

Allison, Dennis O.; Waggoner, E. G.

1990-01-01

Computational predictions of the effects of wing contour modifications on maximum lift and transonic performance were made and verified against low speed and transonic wind tunnel data. This effort was part of a program to improve the maneuvering capability of the EA-6B electronics countermeasures aircraft, which evolved from the A-6 attack aircraft. The predictions were based on results from three computer codes which all include viscous effects: MCARF, a 2-D subsonic panel code; TAWFIVE, a transonic full potential code; and WBPPW, a transonic small disturbance potential flow code. The modifications were previously designed with the aid of these and other codes. The wing modifications consists of contour changes to the leading edge slats and trailing edge flaps and were designed for increased maximum lift with minimum effect on transonic performance. The prediction of the effects of the modifications are presented, with emphasis on verification through comparisons with wind tunnel data from the National Transonic Facility. Attention is focused on increments in low speed maximum lift and increments in transonic lift, pitching moment, and drag resulting from the contour modifications.

Methods to control for unmeasured confounding in pharmacoepidemiology: an overview.

PubMed

Uddin, Md Jamal; Groenwold, Rolf H H; Ali, Mohammed Sanni; de Boer, Anthonius; Roes, Kit C B; Chowdhury, Muhammad A B; Klungel, Olaf H

2016-06-01

Background Unmeasured confounding is one of the principal problems in pharmacoepidemiologic studies. Several methods have been proposed to detect or control for unmeasured confounding either at the study design phase or the data analysis phase. Aim of the Review To provide an overview of commonly used methods to detect or control for unmeasured confounding and to provide recommendations for proper application in pharmacoepidemiology. Methods/Results Methods to control for unmeasured confounding in the design phase of a study are case only designs (e.g., case-crossover, case-time control, self-controlled case series) and the prior event rate ratio adjustment method. Methods that can be applied in the data analysis phase include, negative control method, perturbation variable method, instrumental variable methods, sensitivity analysis, and ecological analysis. A separate group of methods are those in which additional information on confounders is collected from a substudy. The latter group includes external adjustment, propensity score calibration, two-stage sampling, and multiple imputation. Conclusion As the performance and application of the methods to handle unmeasured confounding may differ across studies and across databases, we stress the importance of using both statistical evidence and substantial clinical knowledge for interpretation of the study results.

Applied Self-Statement Modification and Applied Modified Desensitization in the Treatment of Speech Anxiety: The Synergy Hypothesis.

ERIC Educational Resources Information Center

Melanson, Diane C.

A study examined the relative effectiveness and synergistic effect of two treatments for reducing speech anxiety--Self-Statement Modification (SSM), a therapy focused on modification of cognitive behavior; and Modified Desensitization (MD), a therapy focused on physiological variables, utilizing relaxation training, group hierarchy construction,…

Effectiveness of electronic stability control on single-vehicle accidents.

PubMed

Lyckegaard, Allan; Hels, Tove; Bernhoft, Inger Marie

2015-01-01

This study aims at evaluating the effectiveness of electronic stability control (ESC) on single-vehicle injury accidents while controlling for a number of confounders influencing the accident risk. Using police-registered injury accidents from 2004 to 2011 in Denmark with cars manufactured in the period 1998 to 2011 and the principle of induced exposure, 2 measures of the effectiveness of ESC were calculated: The crude odds ratio and the adjusted odds ratio, the latter by means of logistic regression. The logistic regression controlled for a number of confounding factors, of which the following were significant. For the driver: Age, gender, driving experience, valid driving license, and seat belt use. For the vehicle: Year of registration, weight, and ESC. For the accident surroundings: Visibility, light, and location. Finally, for the road: Speed limit, surface, and section characteristics. The present study calculated the crude odds ratio for ESC-equipped cars of getting in a single-vehicle injury accident as 0.40 (95% confidence interval [CI], 0.34-0.47) and the adjusted odds ratio as 0.69 (95% CI, 0.54-0.88). No difference was found in the effectiveness of ESC across the injury severity categories (slight, severe, and fatal). In line with previous results, this study concludes that ESC reduces the risk for single-vehicle injury accidents by 31% when controlling for various confounding factors related to the driver, the car, and the accident surroundings. Furthermore, it is concluded that it is important to control for human factors (at a minimum age and gender) in analyses where evaluations of this type are performed.

Effectiveness of a coordinated and tailored return-to-work intervention for sickness absence beneficiaries with mental health problems.

PubMed

Martin, Marie H T; Nielsen, Maj Britt D; Madsen, Ida E H; Petersen, Signe M A; Lange, Theis; Rugulies, Reiner

2013-12-01

Sickness absence and exclusion from the labour market due to mental health problems (MHPs) is a growing concern in many countries. Knowledge about effective return-to-work (RTW) intervention models is still limited, but a multidisciplinary, coordinated and tailored approach has shown promising results in the context of musculoskeletal disorders. The purpose of this study was to assess the effectiveness of this approach as implemented among sickness absence beneficiaries with MHPs. In a quasi-randomised, controlled trial, we assessed the intervention's effect in terms of time to RTW and labour market status after 1 year. We used two different analytical strategies to compare time to RTW between participants receiving the intervention (n = 88) and those receiving conventional case management (n = 80): (1) a traditional multivariable regression analysis controlling for measured confounding, and (2) an instrumental variable (IV) analysis controlling for unmeasured confounding. The two analytical approaches provided similar results in terms of a longer time to RTW among recipients of the intervention (HR = 0.50; 95 % CI 0.34-0.75), although the estimate provided by the IV-analysis was non-significant (HR = 0.70; 95 % CI 0.23-2.12). After 1 year, more recipients of the intervention than of conventional case management were receiving sickness absence benefits (p = 0.031). The intervention delayed RTW compared to conventional case management, after accounting for measured confounding. The delayed RTW may be due to either implementation or program failure, or both. It may also reflect the complexity of retaining employees with mental health problems in the workplace.

Effects of wing modification on an aircraft's aerodynamic parameters as determined from flight data

NASA Technical Reports Server (NTRS)

Hess, R. A.

1986-01-01

A study of the effects of four wing-leading-edge modifications on a general aviation aircraft's stability and control parameters is presented. Flight data from the basic aircraft configuration and configurations with wing modifications are analyzed to determine each wing geometry's stability and control parameters. The parameter estimates and aerodynamic model forms are obtained using the stepwise regression and maximum likelihood techniques. The resulting parameter estimates and aerodynamic models are verified using vortex-lattice theory and by analysis of each model's ability to predict aircraft behavior. Comparisons of the stability and control derivative estimates from the basic wing and the four leading-edge modifications are accomplished so that the effects of each modification on aircraft stability and control derivatives can be determined.

Modification of Sr on 4004 Aluminum Alloy

NASA Astrophysics Data System (ADS)

Guo, Erjun; Cao, Guojian; Feng, Yicheng; Wang, Liping; Wang, Guojun; Lv, Xinyu

2013-05-01

As a brazing foil, 4004 Al alloy has good welding performance. However, the high Si content decreases the plasticity of the alloy. To improve the plasticity of 4004 Al alloy and subsequently improve the productivity of 4004 Al foil or 434 composite foil, 4004 Al alloy was modified by Al-10%Sr master alloy. Modification effects of an additional amount of Sr, modification temperature, and holding time on 4004 aluminum alloy were studied by orthogonal design. The results showed that the greatest impact parameter of 4004 aluminum alloy modification was the additional amount of Sr, followed by holding time and modification temperature. The optimum modification parameters obtained by orthogonal design were as follows: Sr addition of 0.04%, holding time of 60 min, and modification temperature of 760°C. The effect of Sr addition on modification was analyzed in detail based on orthogonal results. With increasing of Sr addition, elongation of 4004 alloy increased at first, and decreased after reaching the maximum value.

Analyzing the Impacts of Dams on Riparian Ecosystems: A Review of Research Strategies and Their Relevance to the Snake River Through Hells Canyon

PubMed Central

Braatne, Jeffrey H.; Goater, Lori A.; Blair, Charles L.

2007-01-01

River damming provides a dominant human impact on river environments worldwide, and while local impacts of reservoir flooding are immediate, subsequent ecological impacts downstream can be extensive. In this article, we assess seven research strategies for analyzing the impacts of dams and river flow regulation on riparian ecosystems. These include spatial comparisons of (1) upstream versus downstream reaches, (2) progressive downstream patterns, or (3) the dammed river versus an adjacent free-flowing or differently regulated river(s). Temporal comparisons consider (4) pre- versus post-dam, or (5) sequential post-dam conditions. However, spatial comparisons are complicated by the fact that dams are not randomly located, and temporal comparisons are commonly limited by sparse historic information. As a result, comparative approaches are often correlative and vulnerable to confounding factors. To complement these analyses, (6) flow or sediment modifications can be implemented to test causal associations. Finally, (7) process-based modeling represents a predictive approach incorporating hydrogeomorphic processes and their biological consequences. In a case study of Hells Canyon, the upstream versus downstream comparison is confounded by a dramatic geomorphic transition. Comparison of the multiple reaches below the dams should be useful, and the comparison of Snake River with the adjacent free-flowing Salmon River may provide the strongest spatial comparison. A pre- versus post-dam comparison would provide the most direct study approach, but pre-dam information is limited to historic reports and archival photographs. We conclude that multiple study approaches are essential to provide confident interpretations of ecological impacts downstream from dams, and propose a comprehensive study for Hells Canyon that integrates multiple research strategies. PMID:18043964

Quasi-experimental study designs series-paper 6: risk of bias assessment.

PubMed

Waddington, Hugh; Aloe, Ariel M; Becker, Betsy Jane; Djimeu, Eric W; Hombrados, Jorge Garcia; Tugwell, Peter; Wells, George; Reeves, Barney

2017-09-01

Rigorous and transparent bias assessment is a core component of high-quality systematic reviews. We assess modifications to existing risk of bias approaches to incorporate rigorous quasi-experimental approaches with selection on unobservables. These are nonrandomized studies using design-based approaches to control for unobservable sources of confounding such as difference studies, instrumental variables, interrupted time series, natural experiments, and regression-discontinuity designs. We review existing risk of bias tools. Drawing on these tools, we present domains of bias and suggest directions for evaluation questions. The review suggests that existing risk of bias tools provide, to different degrees, incomplete transparent criteria to assess the validity of these designs. The paper then presents an approach to evaluating the internal validity of quasi-experiments with selection on unobservables. We conclude that tools for nonrandomized studies of interventions need to be further developed to incorporate evaluation questions for quasi-experiments with selection on unobservables. Copyright © 2017 Elsevier Inc. All rights reserved.

Influence of social support on health-related quality of life outcomes in head and neck cancer.

PubMed

Karnell, Lucy Hynds; Christensen, Alan J; Rosenthal, Eben L; Magnuson, J Scott; Funk, Gerry F

2007-02-01

Evidence that social support influences health-related quality of life (HRQOL) in oncologic patients could be particularly important for head and neck cancer because this disease can affect speech, eating, and facial aesthetics. Multiple regression analyses were used in this prospective, observational study to determine the association between 394 patients' ratings of perceived post-treatment social support and HRQOL outcomes while controlling for possible confounding variables. Higher social support scores were significantly associated with higher scores in speech (p = .007), aesthetics (p = .015), social disruption (p = .045), and general mental health (p = .016) and with fewer depressive symptoms (p = .023) but not with general physical health (p = .191) or eating (p = .114). The magnitude of differences in the HRQOL outcomes for patients whose social support scores fell in the lowest and highest quartiles were clinically meaningful. Given the association between social support and HRQOL outcomes in this patient population, modification of perceived social support through clinical interventions could improve the survivorship of these patients.

Natural CMT2 Variation Is Associated With Genome-Wide Methylation Changes and Temperature Seasonality

PubMed Central

Shen, Xia; De Jonge, Jennifer; Forsberg, Simon K. G.; Pettersson, Mats E.; Sheng, Zheya; Hennig, Lars; Carlborg, Örjan

2014-01-01

As Arabidopsis thaliana has colonized a wide range of habitats across the world it is an attractive model for studying the genetic mechanisms underlying environmental adaptation. Here, we used public data from two collections of A. thaliana accessions to associate genetic variability at individual loci with differences in climates at the sampling sites. We use a novel method to screen the genome for plastic alleles that tolerate a broader climate range than the major allele. This approach reduces confounding with population structure and increases power compared to standard genome-wide association methods. Sixteen novel loci were found, including an association between Chromomethylase 2 (CMT2) and temperature seasonality where the genome-wide CHH methylation was different for the group of accessions carrying the plastic allele. Cmt2 mutants were shown to be more tolerant to heat-stress, suggesting genetic regulation of epigenetic modifications as a likely mechanism underlying natural adaptation to variable temperatures, potentially through differential allelic plasticity to temperature-stress. PMID:25503602

Does Peer Ability Affect Student Achievement?

ERIC Educational Resources Information Center

Hanushek, Eric A.; Kain, John F.; Markman, Jacob M.; Rivkin, Steven G.

Empirical analysis of peer effects on student achievement has been open to question because of the difficulties of separating peer effects from other confounding influences. While most econometric attention has been directed at issues of simultaneous determination of peer interactions, this paper argues that issues of omitted and mismeasured…

Propensity Score Estimation With Boosted Regression for Evaluating Causal Effects in Observational Studies

ERIC Educational Resources Information Center

McCaffrey, Daniel F.; Ridgeway, Greg; Morral, Andrew R.

2004-01-01

Causal effect modeling with naturalistic rather than experimental data is challenging. In observational studies participants in different treatment conditions may also differ on pretreatment characteristics that influence outcomes. Propensity score methods can theoretically eliminate these confounds for all observed covariates, but accurate…

Effects of Disturbance-induced trauma on foraging by subterranean termites (Isoptera: Rhinotermitidae)

Treesearch

R. J. Woodrow; T. G. Shelton; R. J. Oshiro; J. K. Grace; T. L. Wagner

2008-01-01

Toxicant baiting systems are effective at population suppression against both the Formosan subterranean termite, Coptotermes formosanus Shiraki, and the Eastern subterranean termite, Reticulitermes flavipes (Kollar). However, trap shyness (i.e., station abandonment) is often quoted as a confounding factor affecting their success....

IDENTIFICATION AND INTERPRETATION OF DEVELOPMENTAL NEUROTOXICITY EFFECTS: A REPORT FROM THE ILSI RESEARCH FOUNDATION/RISK SCIENCE INSTITUTE EXPERT WORKING GROUP ON NEURODEVELOPMENTAL ENDPOINTS

EPA Science Inventory

The reliable detection, measurement, and interpretation of treatment-related developmental neurotoxicity (DNT) effects depend on appropriate study design and execution, using scientifically established methodologies, with appropriate controls to minimize confounding factors. App...

Surface modification effects on defect-related photoluminescence in colloidal CdS quantum dots.

PubMed

Lee, TaeGi; Shimura, Kunio; Kim, DaeGwi

2018-05-03

We investigated the effects of surface modification on the defect-related photoluminescence (PL) band in colloidal CdS quantum dots (QDs). A size-selective photoetching process and a surface modification technique with a Cd(OH)2 layer enabled the preparation of size-controlled CdS QDs with high PL efficiency. The Stokes shift of the defect-related PL band before and after the surface modification was ∼1.0 eV and ∼0.63 eV, respectively. This difference in the Stokes shifts suggests that the origin of the defect-related PL band was changed by the surface modification. Analysis by X-ray photoelectron spectroscopy revealed that the surface of the CdS QDs before and after the surface modification was S rich and Cd rich, respectively. These results suggest that Cd-vacancy acceptors and S-vacancy donors affect PL processes in CdS QDs before and after the surface modification, respectively.

Impact of acid and oxidative modifications, single or dual, of sorghum starch on biodegradable films.

PubMed

Biduski, Bárbara; Silva, Francine Tavares da; Silva, Wyller Max da; Halal, Shanise Lisie de Mello El; Pinto, Vania Zanella; Dias, Alvaro Renato Guerra; Zavareze, Elessandra da Rosa

2017-01-01

The objective of this study was to evaluate the effects of acid and oxidation modifications on sorghum starch, as well as the effect of dual modification of starch on the physical, morphological, mechanical, and barrier properties of biodegradable films. The acid modification was performed with 3% lactic acid and the oxidation was performed with 1.5% active chlorine. For dual modification, the acid modification was performed first, followed by oxidation under the same conditions as above. Both films of the oxidized starches, single and dual, had increased stiffness, providing a higher tensile strength and lower elongation when compared to films based on native and single acid modified starches. However, the dual modification increased the water vapor permeability of the films without changing their solubility. The increase in sorghum starch concentration in the filmogenic solution increased the thickness, water vapor permeability, and elongation of the films. Copyright © 2016. Published by Elsevier Ltd.

A systematic literature review on the efficacy–effectiveness gap: comparison of randomized controlled trials and observational studies of glucose-lowering drugs

PubMed Central

Ankarfeldt, Mikkel Z; Adalsteinsson, Erpur; Groenwold, Rolf HH; Ali, M Sanni; Klungel, Olaf H

2017-01-01

Aim To identify a potential efficacy–effectiveness gap and possible explanations (drivers of effectiveness) for differences between results of randomized controlled trials (RCTs) and observational studies investigating glucose-lowering drugs. Methods A systematic literature review was conducted in English language articles published between 1 January, 2000 and 31 January, 2015 describing either RCTs or observational studies comparing glucagon-like peptide-1 analogs (GLP-1) with insulin or comparing dipeptidyl peptidase-4 inhibitors (DPP-4i) with sulfonylurea, all with change in glycated hemoglobin (HbA1c) as outcome. Medline, Embase, Current Content, and Biosis were searched. Information on effect estimates, baseline characteristics of the study population, publication year, study duration, and number of patients, and for observational studies, characteristics related to confounding adjustment and selection- and information bias were extracted. Results From 312 hits, 11 RCTs and 7 observational studies comparing GLP-1 with insulin, and from 474 hits, 16 RCTs and 4 observational studies comparing DPP-4i with sulfonylurea were finally included. No differences were observed in baseline characteristics of the study populations (age, sex, body mass index, time since diagnosis of type 2 diabetes mellitus, and HbA1c) or effect sizes across study designs. Mean effect sizes ranged from −0.43 to 0.91 and from −0.80 to 1.13 in RCTs and observational studies, respectively, comparing GLP-1 with insulin, and from −0.13 to 2.70 and −0.20 to 0.30 in RCTs and observational studies, respectively, comparing DPP-4i and sulfonylurea. Generally, the identified observational studies held potential flaws with regard to confounding adjustment and selection- and information bias. Conclusions Neither potential drivers of effectiveness nor an efficacy–effectiveness gap were identified. However, the limited number of studies and potential problems with confounding adjustment, selection- and information bias in the observational studies, may have hidden a true efficacy-effectiveness gap. PMID:28176959

Hypothetical midlife interventions in women and risk of type 2 diabetes.

PubMed

Danaei, Goodarz; Pan, An; Hu, Frank B; Hernán, Miguel A

2013-01-01

Randomized trials have examined short-term effects of lifestyle interventions for diabetes prevention only among high-risk individuals. Prospective studies have examined the associations between lifestyle factors and diabetes in healthy populations but have not characterized the intervention. We estimated the long-term effects of hypothetical lifestyle interventions on diabetes in a prospective study of healthy women, using the parametric g-formula. Using data from the Nurses' Health Study, we followed 76,402 women from 1984 to 2008. We estimated the risk of type 2 diabetes under eight hypothetical interventions: quitting smoking, losing weight by 5% every 2 years if overweight/obese, exercising at least 30 minutes a day, eating less than three servings a week of red meat, eating at least two servings a day of whole grain, drinking two or more cups of coffee a day, drinking five or more grams of alcohol a day, and drinking less than one serving of soda a week. The 24-year risk of diabetes was 9.6% under no intervention and 4.3% when all interventions were imposed (55% lower risk [95% confidence interval = 47 to 63%]). The most effective interventions were weight loss (24% lower risk), physical activity (19%), and moderate alcohol use (19%). Overweight/obese women would benefit the most, with 10.8 percentage point reduction in 24-year risk of diabetes. The validity of these estimates relies on the absence of unmeasured confounding, measurement error, and model misspecification. A combination of dietary and nondietary lifestyle modifications, begun in midlife or later in relatively healthy women, could have prevented at least half of the cases of type 2 diabetes in this cohort of U.S. women.

Associations of short-term exposure to traffic-related air pollution with cardiovascular and respiratory hospital admissions in London, UK.

PubMed

Samoli, Evangelia; Atkinson, Richard W; Analitis, Antonis; Fuller, Gary W; Green, David C; Mudway, Ian; Anderson, H Ross; Kelly, Frank J

2016-05-01

There is evidence of adverse associations between short-term exposure to traffic-related pollution and health, but little is known about the relative contribution of the various sources and particulate constituents. For each day for 2011-2012 in London, UK over 100 air pollutant metrics were assembled using monitors, modelling and chemical analyses. We selected a priori metrics indicative of traffic sources: general traffic, petrol exhaust, diesel exhaust and non-exhaust (mineral dust, brake and tyre wear). Using Poisson regression models, controlling for time-varying confounders, we derived effect estimates for cardiovascular and respiratory hospital admissions at prespecified lags and evaluated the sensitivity of estimates to multipollutant modelling and effect modification by season. For single day exposure, we found consistent associations between adult (15-64 years) cardiovascular and paediatric (0-14 years) respiratory admissions with elemental and black carbon (EC/BC), ranging from 0.56% to 1.65% increase per IQR change, and to a lesser degree with carbon monoxide (CO) and aluminium (Al). The average of past 7 days EC/BC exposure was associated with elderly (65+ years) cardiovascular admissions. Indicated associations were higher during the warm period of the year. Although effect estimates were sensitive to the adjustment for other pollutants they remained consistent in direction, indicating independence of associations from different sources, especially between diesel and petrol engines, as well as mineral dust. Our results suggest that exhaust related pollutants are associated with increased numbers of adult cardiovascular and paediatric respiratory hospitalisations. More extensive monitoring in urban centres is required to further elucidate the associations. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

A cool experimental approach to explain elevational treelines, but can it explain them?

PubMed

Bader, Maaike Y; Loranger, Hannah; Zotz, Gerhard

2014-09-01

At alpine treeline, trees give way to low-stature alpine vegetation. The main reason may be that tree canopies warm up less in the sun and experience lower average temperatures than alpine vegetation. Low growth temperatures limit tissue formation more than carbon gain, but whether this mechanism universally determines potential treeline elevations is the subject of debate. To study low-temperature limitation in two contrasting treeline tree species, Fajardo and Piper (American Journal of Botany 101: 788-795) grew potted seedlings at ground level or suspended at tree-canopy height (2 m), introducing a promising experimental method for studying the effects of alpine-vegetation and tree-canopy microclimates on tree growth. On the basis of this experiment, the authors concluded that lower temperatures at 2 m caused carbon limitation in one of the species and that treeline-forming mechanisms may thus be taxon-dependent. Here we contest that this important conclusion can be drawn based on the presented experiment, because of confounding effects of extreme root-zone temperature fluctuations and potential drought conditions. To interpret the results of this elegant experiment without logistically challenging technical modifications and to better understand how low temperature leads to treeline formation, studies on effects of fluctuating vs. stable temperatures are badly needed. Other treeline research priorities are interactions between temperature and other climatic factors and differences in microclimate between tree canopies with contrasting morphology and physiology. In spite of our criticism of this particular study, we agree that the development of a universal treeline theory should include continuing explorations of taxon-specific treeline-forming mechanisms. © 2014 Botanical Society of America, Inc.

Associations of short-term exposure to traffic-related air pollution with cardiovascular and respiratory hospital admissions in London, UK

PubMed Central

Samoli, Evangelia; Atkinson, Richard W; Analitis, Antonis; Fuller, Gary W; Green, David C; Mudway, Ian; Anderson, H Ross; Kelly, Frank J

2016-01-01

Objectives There is evidence of adverse associations between short-term exposure to traffic-related pollution and health, but little is known about the relative contribution of the various sources and particulate constituents. Methods For each day for 2011–2012 in London, UK over 100 air pollutant metrics were assembled using monitors, modelling and chemical analyses. We selected a priori metrics indicative of traffic sources: general traffic, petrol exhaust, diesel exhaust and non-exhaust (mineral dust, brake and tyre wear). Using Poisson regression models, controlling for time-varying confounders, we derived effect estimates for cardiovascular and respiratory hospital admissions at prespecified lags and evaluated the sensitivity of estimates to multipollutant modelling and effect modification by season. Results For single day exposure, we found consistent associations between adult (15–64 years) cardiovascular and paediatric (0–14 years) respiratory admissions with elemental and black carbon (EC/BC), ranging from 0.56% to 1.65% increase per IQR change, and to a lesser degree with carbon monoxide (CO) and aluminium (Al). The average of past 7 days EC/BC exposure was associated with elderly (65+ years) cardiovascular admissions. Indicated associations were higher during the warm period of the year. Although effect estimates were sensitive to the adjustment for other pollutants they remained consistent in direction, indicating independence of associations from different sources, especially between diesel and petrol engines, as well as mineral dust. Conclusions Our results suggest that exhaust related pollutants are associated with increased numbers of adult cardiovascular and paediatric respiratory hospitalisations. More extensive monitoring in urban centres is required to further elucidate the associations. PMID:26884048

Differentiating Challenge Reactivity from Psychomotor Activity in Studies of Children’s Psychophysiology: Considerations for Theory and Measurement

PubMed Central

Bush, Nicole R.; Alkon, Abbey; Obradović, Jelena; Stamperdahl, Juliet; Boyce, W. Thomas

2014-01-01

Current methods of assessing children’s physiologic “stress reactivity” may be confounded by psychomotor activity, biasing estimates of the relation between reactivity and health. We examine the joint and independent contributions of psychomotor activity and challenge reactivity during a protocol for children ages 5–6 (N=338). Measures of parasympathetic (RSA) and sympathetic (PEP) reactivity were calculated for social, cognitive, sensory, and emotional challenge tasks. Reactivity was calculated relative to both resting and a paired comparison task that accounted for psychomotor activity effects during each challenge. Results indicated that comparison tasks themselves elicited RSA and PEP responses, and reactivity adjusted for psychomotor activity was incongruent with reactivity calculated using rest. Findings demonstrate the importance of accounting for confounding psychomotor activity effects on physiologic reactivity. PMID:21524757

Comparison between treatment effects in a randomised controlled trial and an observational study using propensity scores in primary care.

PubMed

Stuart, Beth L; Grebel, Louise En; Butler, Christopher C; Hood, Kerenza; Verheij, Theo J M; Little, Paul

2017-09-01

Although randomised controlled trials (RCTs) are considered 'gold standard' evidence, they are not always feasible or appropriate, and may represent a select population. Observational studies provide a useful alternative to enhance applicability, but results can be biased due to confounding. To explore the utility of propensity scores for causal inference in an observational study. Comparison of the effect of amoxicillin on key outcomes in an international RCT and observational study of lower respiratory tract infections. Propensity scores were calculated and applied as probability weights in the analyses. The adjusted results were compared with the effects reported in the RCT. Groups were well balanced in the RCT but significantly imbalanced in the observational study, with evidence of confounding by indication: patients receiving antibiotics tended to be older and more unwell at baseline consultation. In the trial duration of symptoms (hazard ratio 1.06, 95% CI = 0.96 to 1.18) and symptom severity (-0.07, 95% CI = -0.15 to 0.007) did not differ between groups. Weighting by propensity score in the observational study resulted in very similar estimates of effect: duration of symptoms (hazard ratio 1.06, 95% CI = 0.80 to 1.40) and difference for symptom severity (-0.07, 95% CI = -0.34 to 0.20). The observational study, after conditioning on propensity score, echoed the trial results. Provided that detailed information is available on potential sources of confounding, effects of interventions can probably be assessed reasonably well in observational datasets, allowing them to be more directly compared with the results of RCTs. © British Journal of General Practice 2017.

Combining fixed effects and instrumental variable approaches for estimating the effect of psychosocial job quality on mental health: evidence from 13 waves of a nationally representative cohort study.

PubMed

Milner, Allison; Aitken, Zoe; Kavanagh, Anne; LaMontagne, Anthony D; Pega, Frank; Petrie, Dennis

2017-06-23

Previous studies suggest that poor psychosocial job quality is a risk factor for mental health problems, but they use conventional regression analytic methods that cannot rule out reverse causation, unmeasured time-invariant confounding and reporting bias. This study combines two quasi-experimental approaches to improve causal inference by better accounting for these biases: (i) linear fixed effects regression analysis and (ii) linear instrumental variable analysis. We extract 13 annual waves of national cohort data including 13 260 working-age (18-64 years) employees. The exposure variable is self-reported level of psychosocial job quality. The instruments used are two common workplace entitlements. The outcome variable is the Mental Health Inventory (MHI-5). We adjust for measured time-varying confounders. In the fixed effects regression analysis adjusted for time-varying confounders, a 1-point increase in psychosocial job quality is associated with a 1.28-point improvement in mental health on the MHI-5 scale (95% CI: 1.17, 1.40; P < 0.001). When the fixed effects was combined with the instrumental variable analysis, a 1-point increase psychosocial job quality is related to 1.62-point improvement on the MHI-5 scale (95% CI: -0.24, 3.48; P = 0.088). Our quasi-experimental results provide evidence to confirm job stressors as risk factors for mental ill health using methods that improve causal inference. © The Author 2017. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Case-control vaccine effectiveness studies: Preparation, design, and enrollment of cases and controls.

PubMed

Verani, Jennifer R; Baqui, Abdullah H; Broome, Claire V; Cherian, Thomas; Cohen, Cheryl; Farrar, Jennifer L; Feikin, Daniel R; Groome, Michelle J; Hajjeh, Rana A; Johnson, Hope L; Madhi, Shabir A; Mulholland, Kim; O'Brien, Katherine L; Parashar, Umesh D; Patel, Manish M; Rodrigues, Laura C; Santosham, Mathuram; Scott, J Anthony; Smith, Peter G; Sommerfelt, Halvor; Tate, Jacqueline E; Victor, J Chris; Whitney, Cynthia G; Zaidi, Anita K; Zell, Elizabeth R

2017-06-05

Case-control studies are commonly used to evaluate effectiveness of licensed vaccines after deployment in public health programs. Such studies can provide policy-relevant data on vaccine performance under 'real world' conditions, contributing to the evidence base to support and sustain introduction of new vaccines. However, case-control studies do not measure the impact of vaccine introduction on disease at a population level, and are subject to bias and confounding, which may lead to inaccurate results that can misinform policy decisions. In 2012, a group of experts met to review recent experience with case-control studies evaluating the effectiveness of several vaccines; here we summarize the recommendations of that group regarding best practices for planning, design and enrollment of cases and controls. Rigorous planning and preparation should focus on understanding the study context including healthcare-seeking and vaccination practices. Case-control vaccine effectiveness studies are best carried out soon after vaccine introduction because high coverage creates strong potential for confounding. Endpoints specific to the vaccine target are preferable to non-specific clinical syndromes since the proportion of non-specific outcomes preventable through vaccination may vary over time and place, leading to potentially confusing results. Controls should be representative of the source population from which cases arise, and are generally recruited from the community or health facilities where cases are enrolled. Matching of controls to cases for potential confounding factors is commonly used, although should be reserved for a limited number of key variables believed to be linked to both vaccination and disease. Case-control vaccine effectiveness studies can provide information useful to guide policy decisions and vaccine development, however rigorous preparation and design is essential. Published by Elsevier Ltd.

Treatment effect heterogeneity for univariate subgroups in clinical trials: Shrinkage, standardization, or else

PubMed Central

Varadhan, Ravi; Wang, Sue-Jane

2016-01-01

Treatment effect heterogeneity is a well-recognized phenomenon in randomized controlled clinical trials. In this paper, we discuss subgroup analyses with prespecified subgroups of clinical or biological importance. We explore various alternatives to the naive (the traditional univariate) subgroup analyses to address the issues of multiplicity and confounding. Specifically, we consider a model-based Bayesian shrinkage (Bayes-DS) and a nonparametric, empirical Bayes shrinkage approach (Emp-Bayes) to temper the optimism of traditional univariate subgroup analyses; a standardization approach (standardization) that accounts for correlation between baseline covariates; and a model-based maximum likelihood estimation (MLE) approach. The Bayes-DS and Emp-Bayes methods model the variation in subgroup-specific treatment effect rather than testing the null hypothesis of no difference between subgroups. The standardization approach addresses the issue of confounding in subgroup analyses. The MLE approach is considered only for comparison in simulation studies as the “truth” since the data were generated from the same model. Using the characteristics of a hypothetical large outcome trial, we perform simulation studies and articulate the utilities and potential limitations of these estimators. Simulation results indicate that Bayes-DS and Emp-Bayes can protect against optimism present in the naïve approach. Due to its simplicity, the naïve approach should be the reference for reporting univariate subgroup-specific treatment effect estimates from exploratory subgroup analyses. Standardization, although it tends to have a larger variance, is suggested when it is important to address the confounding of univariate subgroup effects due to correlation between baseline covariates. The Bayes-DS approach is available as an R package (DSBayes). PMID:26485117

A Framework for Estimating Causal Effects in Latent Class Analysis: Is There a Causal Link Between Early Sex and Subsequent Profiles of Delinquency?

PubMed Central

Lanza, Stephanie T.; Coffman, Donna L.

2013-01-01

Prevention scientists use latent class analysis (LCA) with increasing frequency to characterize complex behavior patterns and profiles of risk. Often, the most important research questions in these studies involve establishing characteristics that predict membership in the latent classes, thus describing the composition of the subgroups and suggesting possible points of intervention. More recently, prevention scientists have begun to adopt modern methods for drawing causal inference from observational data because of the bias that can be introduced by confounders. This same issue of confounding exists in any analysis of observational data, including prediction of latent class membership. This study demonstrates a straightforward approach to causal inference in LCA that builds on propensity score methods. We demonstrate this approach by examining the causal effect of early sex on subsequent delinquency latent classes using data from 1,890 adolescents in 11th and 12th grade from wave I of the National Longitudinal Study of Adolescent Health. Prior to the statistical adjustment for potential confounders, early sex was significantly associated with delinquency latent class membership for both genders (p=0.02). However, the propensity score adjusted analysis indicated no evidence for a causal effect of early sex on delinquency class membership (p=0.76) for either gender. Sample R and SAS code is included in an Appendix in the ESM so that prevention scientists may adopt this approach to causal inference in LCA in their own work. PMID:23839479

A framework for estimating causal effects in latent class analysis: is there a causal link between early sex and subsequent profiles of delinquency?

PubMed

Butera, Nicole M; Lanza, Stephanie T; Coffman, Donna L

2014-06-01

Prevention scientists use latent class analysis (LCA) with increasing frequency to characterize complex behavior patterns and profiles of risk. Often, the most important research questions in these studies involve establishing characteristics that predict membership in the latent classes, thus describing the composition of the subgroups and suggesting possible points of intervention. More recently, prevention scientists have begun to adopt modern methods for drawing causal inference from observational data because of the bias that can be introduced by confounders. This same issue of confounding exists in any analysis of observational data, including prediction of latent class membership. This study demonstrates a straightforward approach to causal inference in LCA that builds on propensity score methods. We demonstrate this approach by examining the causal effect of early sex on subsequent delinquency latent classes using data from 1,890 adolescents in 11th and 12th grade from wave I of the National Longitudinal Study of Adolescent Health. Prior to the statistical adjustment for potential confounders, early sex was significantly associated with delinquency latent class membership for both genders (p = 0.02). However, the propensity score adjusted analysis indicated no evidence for a causal effect of early sex on delinquency class membership (p = 0.76) for either gender. Sample R and SAS code is included in an Appendix in the ESM so that prevention scientists may adopt this approach to causal inference in LCA in their own work.

Effects of environmental lead pollution on blood lead and sex hormone levels among occupationally exposed group in an E-waste dismantling area.

PubMed

Yang, Yan; Lu, Xiao Song; Li, Ding Long; Yu, Yun Jiang

2013-06-01

To study the effects of environmental multi-media lead pollution on blood lead and sex hormone levels among lead exposed males engaged in E-waste dismantling, and the correlation between confounding factors and sex hormone levels. An E-waste dismantling area in Taizhou of Zhejiang Province was selected as the research site. One hundred and fifty two samples were collected from the groundwater, soil, rice, corn, chicken, and pork in the dismantling area. The effects of the multi-media lead pollution on the male blood lead and sex hormone levels of FSH, LH, and T, as well as the correlation with confounding factors, were studied. The blood lead concentrations in the males aged under 31, from 31 to 45 and from 46 to 60 were 98.55, 100.23, and 101.45 μg/L, respectively. Of all the environmental media lead exposures, the groundwater, rice and soil were main contributing factors to the lead accumulation in humans. FSH and LH levels increased with the age while the T levels decreased with the age instead. There was a significant correlation between the FSH and LH levels and wearing masks. There was correlation between the FSH, LH, and T levels, and the mean values of lead concentrations in environmental media, and the sex hormone levels were correlated with the confounding factor of wearing masks. Copyright © 2013 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

The Gratton effect remains after controlling for contingencies and stimulus repetitions

PubMed Central

Blais, Chris; Stefanidi, Aikaterini; Brewer, Gene A.

2014-01-01

Highlights: The conflict monitoring hypothesis signals the need for cognitive controlThe Gratton effect is a key result attributed to the conflict monitoring hypothesisSome argue that controlling binding confounds eliminates the Gratton effect A Gratton effect remains in a vocal Stroop task after eliminating confounds The Gratton effect, the observation that the size of the Stroop effect is larger following a congruent trial compared to an incongruent trial, is one pivotal observation in support of the conflict-monitoring hypothesis. Previous reports have demonstrated that non-conflict components, such as feature binding, also contribute to this effect. Critically, Schmidt and De Houwer (2011) report a flanker task and a button-press Stroop task suggesting that there is no conflict adaptation in the Gratton effect; it is entirely caused by feature binding. The current investigation attempts to replicate and extend this important finding across two experiments using a canonical four-choice Stroop task with vocal responses. In contrast to Schmidt and De Houwer, we observe reliable conflict adaptation after controlling for feature binding. We argue that the overall strength of conflict is critical for determining whether a conflict adaptation component will remain in the Gratton effect after explaining binding components. PMID:25386151

Interventional effects for mediation analysis with multiple mediators

PubMed Central

Vansteelandt, Stijn; Daniel, Rhian M.

2016-01-01

The mediation formula for the identification of natural (in)direct effects has facilitated mediation analyses that better respect the nature of the data, with greater consideration of the need for confounding control. The default assumptions on which it relies are strong, however. In particular, they are known to be violated when confounders of the mediator–outcome association are affected by the exposure. This complicates extensions of counterfactual-based mediation analysis to settings that involve repeatedly measured mediators, or multiple correlated mediators. VanderWeele, Vansteelandt, and Robins21 introduced so-called interventional (in)direct effects. These can be identified under much weaker conditions than natural (in)direct effects, but have the drawback of not adding up to the total effect. In this article, we adapt their proposal in order to achieve an exact decomposition of the total effect, and extend it to the multiple mediator setting. Interestingly, the proposed effects capture the path-specific effects of an exposure on an outcome that are mediated by distinct mediators, even when – as often – the structural dependence between the multiple mediators is unknown; for instance, when the direction of the causal effects between the mediators is unknown, or there may be unmeasured common causes of the mediators. PMID:27922534

Interventional Effects for Mediation Analysis with Multiple Mediators.

PubMed

Vansteelandt, Stijn; Daniel, Rhian M

2017-03-01

The mediation formula for the identification of natural (in)direct effects has facilitated mediation analyses that better respect the nature of the data, with greater consideration of the need for confounding control. The default assumptions on which it relies are strong, however. In particular, they are known to be violated when confounders of the mediator-outcome association are affected by the exposure. This complicates extensions of counterfactual-based mediation analysis to settings that involve repeatedly measured mediators, or multiple correlated mediators. VanderWeele, Vansteelandt, and Robins introduced so-called interventional (in)direct effects. These can be identified under much weaker conditions than natural (in)direct effects, but have the drawback of not adding up to the total effect. In this article, we adapt their proposal to achieve an exact decomposition of the total effect, and extend it to the multiple mediator setting. Interestingly, the proposed effects capture the path-specific effects of an exposure on an outcome that are mediated by distinct mediators, even when-as often-the structural dependence between the multiple mediators is unknown, for instance, when the direction of the causal effects between the mediators is unknown, or there may be unmeasured common causes of the mediators.

Ecological Effects of Weather Modification: A Problem Analysis.

ERIC Educational Resources Information Center

Cooper, Charles F.; Jolly, William C.

This publication reviews the potential hazards to the environment of weather modification techniques as they eventually become capable of producing large scale weather pattern modifications. Such weather modifications could result in ecological changes which would generally require several years to be fully evident, including the alteration of…

Interpretational Confounding or Confounded Interpretations of Causal Indicators?

ERIC Educational Resources Information Center

Bainter, Sierra A.; Bollen, Kenneth A.

2014-01-01

In measurement theory, causal indicators are controversial and little understood. Methodological disagreement concerning causal indicators has centered on the question of whether causal indicators are inherently sensitive to interpretational confounding, which occurs when the empirical meaning of a latent construct departs from the meaning…

Methodological guidelines for developing accident modification functions.

PubMed

Elvik, Rune

2015-07-01

This paper proposes methodological guidelines for developing accident modification functions. An accident modification function is a mathematical function describing systematic variation in the effects of road safety measures. The paper describes ten guidelines. An example is given of how to use the guidelines. The importance of exploratory analysis and an iterative approach in developing accident modification functions is stressed. The example shows that strict compliance with all the guidelines may be difficult, but represents a level of stringency that should be strived for. Currently the main limitations in developing accident modification functions are the small number of good evaluation studies and the often huge variation in estimates of effect. It is therefore still not possible to develop accident modification functions for very many road safety measures. Copyright © 2015 Elsevier Ltd. All rights reserved.

An Investigation of the Aerodynamic Characteristics of an 0.08-Scale Model of the Chance Vought XF7U-1 Airplane in the Langley High-Speed 7- by 10-Foot Tunnel. Part V - Wing-Alone Tests and Effect of Modifications to the Vertical Fins, Speed Brakes, and Fuselage TED No. NACA DE308. Part V; Wing-Alone Tests and Effect of Modifications to the Vertical Fins, Speed Brakes, and Fuselage, TED No. NACA DE308

NASA Technical Reports Server (NTRS)

Kuhri, Richard E.; Myers, Boyd C., II

1947-01-01

Tests have been conducted in the Langley high-speed 7- by 10-foot tunnel over a Mach number range from 0.40 to 0.91 to determine the stability and control characteristics of an 0.08-scale model of the Chance Vought XF7U-1 airplane. The wing-alone tests and the effect of the various vertical-fin modifications, speed-brake modifications, and fuselage modifications on the aerodynamic characteristics in pitch and yaw are presented in the present paper with a limited analysis of the results. Also included are tuft studies of the flow for some of the modifications tested.

Methodological issues in studies of air pollution and reproductive health.

PubMed

Woodruff, Tracey J; Parker, Jennifer D; Darrow, Lyndsey A; Slama, Rémy; Bell, Michelle L; Choi, Hyunok; Glinianaia, Svetlana; Hoggatt, Katherine J; Karr, Catherine J; Lobdell, Danelle T; Wilhelm, Michelle

2009-04-01

In the past decade there have been an increasing number of scientific studies describing possible effects of air pollution on perinatal health. These papers have mostly focused on commonly monitored air pollutants, primarily ozone (O(3)), particulate matter (PM), sulfur dioxide (SO(2)), carbon monoxide (CO), and nitrogen dioxide (NO(2)), and various indices of perinatal health, including fetal growth, pregnancy duration, and infant mortality. While most published studies have found some marker of air pollution related to some types of perinatal outcomes, variability exists in the nature of the pollutants and outcomes associated. Synthesis of the findings has been difficult for various reasons, including differences in study design and analysis. A workshop was held in September 2007 to discuss methodological differences in the published studies as a basis for understanding differences in study findings and to identify priorities for future research, including novel approaches for existing data. Four broad topic areas were considered: confounding and effect modification, spatial and temporal exposure variations, vulnerable windows of exposure, and multiple pollutants. Here we present a synopsis of the methodological issues and challenges in each area and make recommendations for future study. Two key recommendations include: (1) parallel analyses of existing data sets using a standardized methodological approach to disentangle true differences in associations from methodological differences among studies; and (2) identification of animal studies to inform important mechanistic research gaps. This work is of critical public health importance because of widespread exposure and because perinatal outcomes are important markers of future child and adult health.

Automatic Online Motor Control Is Intact in Parkinson's Disease With and Without Perceptual Awareness.

PubMed

Merritt, Kate E; Seergobin, Ken N; Mendonça, Daniel A; Jenkins, Mary E; Goodale, Melvyn A; MacDonald, Penny A

2017-01-01

In the double-step paradigm, healthy human participants automatically correct reaching movements when targets are displaced. Motor deficits are prominent in Parkinson's disease (PD) patients. In the lone investigation of online motor correction in PD using the double-step task, a recent study found that PD patients performed unconscious adjustments appropriately but seemed impaired for consciously-perceived modifications. Conscious perception of target movement was achieved by linking displacement to movement onset. PD-related bradykinesia disproportionately prolonged preparatory phases for movements to original target locations for patients, potentially accounting for deficits. Eliminating this confound in a double-step task, we evaluated the effect of conscious awareness of trajectory change on online motor corrections in PD. On and off dopaminergic therapy, PD patients ( n = 14) and healthy controls ( n = 14) reached to peripheral visual targets that remained stationary or unexpectedly moved during an initial saccade. Saccade latencies in PD are comparable to controls'. Hence, target displacements occurred at equal times across groups. Target jump size affected conscious awareness, confirmed in an independent target displacement judgment task. Small jumps were subliminal, but large target displacements were consciously perceived. Contrary to the previous result, PD patients performed online motor corrections normally and automatically, irrespective of conscious perception. Patients evidenced equivalent movement durations for jump and stay trials, and trajectories for patients and controls were identical, irrespective of conscious perception. Dopaminergic therapy had no effect on performance. In summary, online motor control is intact in PD, unaffected by conscious perceptual awareness. The basal ganglia are not implicated in online corrective responses.

Automatic Online Motor Control Is Intact in Parkinson’s Disease With and Without Perceptual Awareness

PubMed Central

Seergobin, Ken N.; Mendonça, Daniel A.

2017-01-01

Abstract In the double-step paradigm, healthy human participants automatically correct reaching movements when targets are displaced. Motor deficits are prominent in Parkinson’s disease (PD) patients. In the lone investigation of online motor correction in PD using the double-step task, a recent study found that PD patients performed unconscious adjustments appropriately but seemed impaired for consciously-perceived modifications. Conscious perception of target movement was achieved by linking displacement to movement onset. PD-related bradykinesia disproportionately prolonged preparatory phases for movements to original target locations for patients, potentially accounting for deficits. Eliminating this confound in a double-step task, we evaluated the effect of conscious awareness of trajectory change on online motor corrections in PD. On and off dopaminergic therapy, PD patients (n = 14) and healthy controls (n = 14) reached to peripheral visual targets that remained stationary or unexpectedly moved during an initial saccade. Saccade latencies in PD are comparable to controls’. Hence, target displacements occurred at equal times across groups. Target jump size affected conscious awareness, confirmed in an independent target displacement judgment task. Small jumps were subliminal, but large target displacements were consciously perceived. Contrary to the previous result, PD patients performed online motor corrections normally and automatically, irrespective of conscious perception. Patients evidenced equivalent movement durations for jump and stay trials, and trajectories for patients and controls were identical, irrespective of conscious perception. Dopaminergic therapy had no effect on performance. In summary, online motor control is intact in PD, unaffected by conscious perceptual awareness. The basal ganglia are not implicated in online corrective responses. PMID:29085900

Assisted reproductive technology, epigenetics, and long-term health: a developmental time bomb still ticking.

PubMed

Grace, Kristen S; Sinclair, Kevin D

2009-09-01

Live birthrates following assisted reproduction account for 1 to 3% of pregnancies in developed countries, and these figures seem set to rise. Concerns regarding the safe use of assisted reproductive technology (ART) for the treatment of infertility have been voiced for several years, yet, to date, the vast majority of children conceived using these techniques are apparently normal. Controversy surrounding reports of epigenetic alterations to genomic imprinting following human ART in recent years has fueled the ongoing debate. In contrast, both the incidence and severity of such anomalies are more apparent following ART in comparative animal species. The reasons for this are not known. By and large, the confounding effects of infertility and advanced maternal age do not apply to animal studies, which report better pregnancy rates following embryo transfer. Perhaps the incidence of imprinting disorders is increased when procedures such as ovarian stimulation, in vitro maturation, or both are used in conjunction with extended periods of embryo culture; this frequently occurs in animal but rarely in human ART. The focus of attention on imprinting, however, may have served to distract the scientific community from more subtle epigenetic modifications to nonimprinted loci in gametes and the preimplantation embryo, with health-related consequences that do not manifest until adulthood. Accumulating evidence from animal studies indicates that such effects, not yet apparent in human subjects, exist; and this may ultimately transpire to be the true developmental legacy of human ART. This article discusses these issues in the context of epigenetic and developmental abnormalities following ART in animals. Thieme Medical Publishers.

Periodontal inflamed surface area and C-reactive protein as predictors of HbA1c: a study in Indonesia.

PubMed

Susanto, Hendri; Nesse, Willem; Dijkstra, Pieter U; Hoedemaker, Evelien; van Reenen, Yvonne Huijser; Agustina, Dewi; Vissink, Arjan; Abbas, Frank

2012-08-01

Periodontitis may exert an infectious and inflammatory burden, evidenced by increased C-reactive protein (CRP). This burden may impair blood glucose control (HbA1c). The aim of our study was to analyze whether periodontitis severity as measured with the periodontal inflamed surface area (PISA) and CRP predict HbA1c levels in a group of healthy Indonesians and a group of Indonesians treated for type 2 diabetes mellitus (DM2). A full-mouth periodontal examination, including probing pocket depth, gingival recession, clinical attachment loss, plaque index and bleeding on probing, was performed in 132 healthy Indonesians and 101 Indonesians treated for DM2. Using these data, PISA was calculated. In addition, HbA1c and CRP were analyzed. A validated questionnaire was used to assess smoking, body mass index (BMI), education and medical conditions. In regression analyses, it was assessed whether periodontitis severity and CRP predict HbA1c, controlling for confounding and effect modification (i.e., age, sex, BMI, pack years, and education). In healthy Indonesians, PISA and CRP predicted HbA1c as did age, sex, and smoking. In Indonesians treated for DM2, PISA did not predict HbA1c. Periodontitis may impair blood glucose regulation in healthy Indonesians in conjunction with elevated CRP levels. The potential effect of periodontitis on glucose control in DM2 patients may be masked by DM2 treatment. periodontitis may impair blood glucose control through exerting an inflammatory and infectious burden evidenced by increased levels of CRP.

Behavior modification therapy in hyperactive children. Research and clinical implications.

PubMed

Wolraich, M L

1979-09-01

One hundred fifty-seven studies employing behavior modification in the management of hyperactive and disruptive children were reviewed. The studies were analyzed against standards of scientific validity. The review found: (1) behavior modification was effective in alleviating problem behaviors; (2) token programs were the most commonly used; (3) both positive reinforcement and punishment were effective; positive reinforcement, however, had the advantage of improving self-esteem; (4) behavioral problems occurring in the home most likely require a home-based program; (5) behavior modification and stimulant medication can be used simultaneously, often with additive effects; and (6) long-term benefits beyond one year have not been assessed.

Effectiveness and confounding factors of penetrating astigmatic keratotomy in clinical practice

PubMed Central

Yen, Chu-Yu; Tseng, Gow-Lieng

2018-01-01

Abstract Rationale: Penetrating astigmatic keratotomy (penetrating AK) is a well-known method to correct corneal astigmatism but rarely be performed nowadays. This article reevaluated the clinical effectiveness and confounding factors of penetrating AK. Patient concerns: Penetrating AK has been introduced to serve as one alternative operation for astigmatism correction, and is thought to have the potential advantage of being more affordable and easy to perform. The purpose of our study is to evaluate the effectiveness and confounding factors of penetrating AK. Diagnoses: The chart of 95 patients with corneal astigmatism (range: 0.75–3.25 diopters [D]) who received penetrating AK from January 2014 to December 2016 was collected. The corneal astigmatism were measured by an autokeratometer (Topcon KR8100PA topographer-autorefractor), and repeated with manual keratometer in low reproducibility cases. Interventions: All patients received penetrating AK by an experienced ophthalmologist (Dr. Gow-Lieng Tseng, MD, PHD) in the operation room. Among which, 66 patients received penetrating AK with phacoemulsification simultaneously (group A), whereas 29 patients received penetrating AK at least 3 months after phacoemulsification (group B). After excluding the patients combined with other procedures or lost followed up, 79 patients are remaining for analysis. The outcome was evaluated by net correction, the difference between preoperative corneal astigmatism (PCA) and residual corneal astigmatism (RCA). Two sample t tests and Pearson test were used for effectiveness evaluation. For confounding factors, multivariate linear regression was used for statistical analysis. Outcomes: The mean preoperative and postoperative refractive cylinders were 1.97 ± 0.77 and 1.08 ± 0.64 D, respectively, in group A and 2.62 ± 1.05 and 1.51 ± 0.89 D in group B. There were no statistically significant differences in net correction between these two groups (0.9 ± 0.66 vs. 1.1 ± 0.69, P = .214). Higher PCA were associated with higher net correction in both group A (P = .002) and group B (P = .019). Compound myopic astigmatism caused less net correction than others only in group A (P = 0.031). Lessons: Penetrating AK is an accessible, affordable, and effective way to correct corneal astigmatism. The results of this procedure are comparable to modern methods in patients with low to moderate corneal astigmatism. PMID:29369200

The Effects of Breastfeeding Exclusivity on Early Childhood Outcomes

PubMed Central

Foster, E. Michael

2014-01-01

Objectives. We examined the relationship between breastfeeding exclusivity and duration and children’s health and cognitive outcomes at ages 2 and 4 years. Methods. We used the Early Childhood Longitudinal Study—Birth Cohort, a nationally representative sample of 10 700 children born in the United States in 2001. Parent interviews and child assessments were conducted in measurement waves at 9 months, 2 years, 4 years, and in kindergarten, with the focus on ages 2 and 4 years. We employed propensity scores as a means of adjusting for confounding involving observed characteristics. Results. Outcome analyses using propensity scores showed some small effects of breastfeeding on key outcomes at age 4 years but not at age 2 years. Effects appeared to be concentrated in reading and cognitive outcomes. Overall, we found no consistent evidence for dosage effects of breastfeeding exclusivity. Our sensitivity analyses revealed that a small amount of unobserved confounding could be responsible for the resulting benefits. Conclusions. Our study revealed little or no effect of breastfeeding exclusivity and duration on key child outcomes. PMID:24354838

The differential effects of tangible rewards and praise on intrinsic motivation: A comparison of cognitive evaluation theory and operant theory.

PubMed

Carton, J S

1996-01-01

Substantial research indicates that tangible rewards, such as money, prizes, and tokens, decrease response rates by undermining intrinsic motivation. In contrast, praise appears to increase response rates by enhancing intrinsic motivation. Based on their interpretation of available evidence, many social-cognitive researchers warn not to use tangible rewards in applied settings and to use praise instead. Furthermore, they suggest that the differential effects of the two types of rewards on intrinsic motivation cannot be explained using principles of operant psychology. Cognitive evaluation theory provides one of the most recent and widely cited social-cognitive explanations for the different effects of the two types of rewards on intrinsic motivation (Deci & Ryan, 1985). However, a review of existing research found little support for the explanations based on this theory and revealed three potential confounding effects: (a) temporal contiguity, (b) the number of reward administrations, and (c) discriminative stimuli associated with reward availability. These three confounding factors provide explanations for the effects of tangible rewards and praise on intrinsic motivation that are consistent with principles of operant psychology.

The differential effects of tangible rewards and praise on intrinsic motivation: A comparison of cognitive evaluation theory and operant theory

PubMed Central

Carton, John S.

1996-01-01

Substantial research indicates that tangible rewards, such as money, prizes, and tokens, decrease response rates by undermining intrinsic motivation. In contrast, praise appears to increase response rates by enhancing intrinsic motivation. Based on their interpretation of available evidence, many social-cognitive researchers warn not to use tangible rewards in applied settings and to use praise instead. Furthermore, they suggest that the differential effects of the two types of rewards on intrinsic motivation cannot be explained using principles of operant psychology. Cognitive evaluation theory provides one of the most recent and widely cited social-cognitive explanations for the different effects of the two types of rewards on intrinsic motivation (Deci & Ryan, 1985). However, a review of existing research found little support for the explanations based on this theory and revealed three potential confounding effects: (a) temporal contiguity, (b) the number of reward administrations, and (c) discriminative stimuli associated with reward availability. These three confounding factors provide explanations for the effects of tangible rewards and praise on intrinsic motivation that are consistent with principles of operant psychology. PMID:22478261

The Intention Interference Effect: The Difficulty of Ignoring What You Intend to Do

PubMed Central

Cohen, Anna-Lisa; Kantner, Justin; Dixon, Roger A.; Lindsay, D. Stephen

2013-01-01

Intentions have been shown to be more accessible (e.g., more quickly and accurately recalled) compared to other sorts of to-be-remembered information; a result termed an intention superiority effect (Goschke & Kuhl, 1993). In the current study, we demonstrate an intention interference effect (IIE) in which colour-naming performance in a Stroop task was slower for words belonging to an intention that participants had to remember to carry out (Do the Task condition) versus an intention that did not have to be executed (Ignore the Task condition). In previous work (e.g., Cohen et al., 2005), having a prospective intention in mind was confounded with carrying a memory load. In Experiment 1, we added a digit-retention task to control for effects of cognitive load. In Experiment 2, we eliminated the memory confound in a new way, by comparing intention-related and control words within each trial. Results from both Experiments 1 and 2 revealed an intention interference effect suggesting that interference is very specific to the intention, not just to a memory load. PMID:21592940

Long-term integrated studies show complex and surprising effects of climate change in northern hardwood forests

Treesearch

Peter M. Groffman; Lindsey Rustad; Pamela H. Templer; John Campbell; Lynn M. Christenson; Nina K. Lany; Anne M. Socci; Matthew A. Vadeboncoeur; Paul Schaberg; Geoffrey F. Wilson; Charles T. Driscoll; Timothy J. Fahey; Melany C. Fisk; Christine L. Goodale; Mark B. Green; Steven P. Hamburg; Chris E. Johnson; Myron J. Mitchell; Jennifer L. Morse; Linda H. Pardo; Nicholas L. Rodenhouse

2012-01-01

Evaluations of the local effects of global change are often confounded by the interactions of natural and anthropogenic factors that overshadow the effects of climate changes on ecosystems. Long-term watershed and natural elevation gradient studies at the Hubbard Brook Experimental Forest and in the surrounding region show surprising results demonstrating the effects...

The Effects of Age on Second Language Grammar and Speech Production

ERIC Educational Resources Information Center

Huang, Becky H.

2014-01-01

The current study examined the age of learning effect on second language (L2) acquisition. The research goals of the study were twofold: to test whether there is an independent age effect controlling for other potentially confounding variables, and to clarify the age effect across L2 grammar and speech production domains. The study included 118…

The Effects of Teacher Behaviors on Students' Inclination to Inquire and Lifelong Learning

ERIC Educational Resources Information Center

Loes, Chad N.; Saichaie, Kem; Padget, Ryan D.; Pascarella, Ernest T.

2012-01-01

This study estimated the effects of teacher organization, clarity, classroom challenge and faculty expectations, support, and prompt feedback on students' inclination to inquire and lifelong learning during the first year of college. Controlling for a battery of potential confounding influences, teacher organization was positively associated with…

Is Religion Not Prosocial at All? Comment on Galen (2012)

ERIC Educational Resources Information Center

Saroglou, Vassilis

2012-01-01

Galen (2012), critically reviewing recent research on religion and prosociality, concludes that the religious prosociality hypothesis is a (congruence) fallacy. The observed effects are not real: They only reflect stereotypes and ingroup favoritism, are due to secular psychological effects, are inconsistent, and confound (e.g., by ignoring…

On the Bias-Amplifying Effect of Near Instruments in Observational Studies

ERIC Educational Resources Information Center

Steiner, Peter M.; Kim, Yongnam

2014-01-01

In contrast to randomized experiments, the estimation of unbiased treatment effects from observational data requires an analysis that conditions on all confounding covariates. Conditioning on covariates can be done via standard parametric regression techniques or nonparametric matching like propensity score (PS) matching. The regression or…

Sensitivity analysis for mistakenly adjusting for mediators in estimating total effect in observational studies.

PubMed

Wang, Tingting; Li, Hongkai; Su, Ping; Yu, Yuanyuan; Sun, Xiaoru; Liu, Yi; Yuan, Zhongshang; Xue, Fuzhong

2017-11-20

In observational studies, epidemiologists often attempt to estimate the total effect of an exposure on an outcome of interest. However, when the underlying diagram is unknown and limited knowledge is available, dissecting bias performances is essential to estimating the total effect of an exposure on an outcome when mistakenly adjusting for mediators under logistic regression. Through simulation, we focused on six causal diagrams concerning different roles of mediators. Sensitivity analysis was conducted to assess the bias performances of varying across exposure-mediator effects and mediator-outcome effects when adjusting for the mediator. Based on the causal relationships in the real world, we compared the biases of varying across the effects of exposure-mediator with those of varying across the effects of mediator-outcome when adjusting for the mediator. The magnitude of the bias was defined by the difference between the estimated effect (using logistic regression) and the total effect of the exposure on the outcome. In four scenarios (a single mediator, two series mediators, two independent parallel mediators or two correlated parallel mediators), the biases of varying across the effects of exposure-mediator were greater than those of varying across the effects of mediator-outcome when adjusting for the mediator. In contrast, in two other scenarios (a single mediator or two independent parallel mediators in the presence of unobserved confounders), the biases of varying across the effects of exposure-mediator were less than those of varying across the effects of mediator-outcome when adjusting for the mediator. The biases were more sensitive to the variation of effects of exposure-mediator than the effects of mediator-outcome when adjusting for the mediator in the absence of unobserved confounders, while the biases were more sensitive to the variation of effects of mediator-outcome than those of exposure-mediator in the presence of an unobserved confounder. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Prenatal maternal stress in relation to the effects of prenatal lead exposure on toddler cognitive development.

PubMed

Zhou, Leilei; Xu, Jian; Zhang, Jinsong; Yan, Chonghuai; Lin, Yanfen; Jia, Yinan; Hu, Wenjing

2017-03-01

To evaluate the effects of maternal lead exposure during pregnancy on toddler cognitive development and the potential effect modification by maternal stress. We conducted a prospective birth-cohort study in Shanghai from 2010 to 2012 and investigated 225 mother-infant pairs. The mothers were recruited in mid-to-late pregnancy and children were followed up until 24-36 months old. A self-administered Symptom Checklist-90-Revised Scale (SCL-90-R) was used to assess maternal emotional stress during pregnancy. Maternal whole blood lead levels were measured during gestational weeks 28-36. The toddlers' cognitive levels were assessed using the Gesell Development Scale. Multiple linear regression models were established to explore the main effects of prenatal lead exposure on toddlers' cognitive abilities and the modifying effects of maternal stress. Covariate information was collected through interviews, questionnaires and medical records. The mean maternal blood lead concentration was 3.30 (95%CI: 3.05, 3.57) μg/dL. After adjusting for relevant confounders, no significant associations of maternal blood lead concentrations with toddlers' cognitive levels were observed in all five domains of the Gesell scale (P>0.05). However, the interaction between prenatal maternal blood lead and stress was significant in the domains of adaptive behavior, language and social behavior. When stratified by maternal stress levels, compared with non-significant associations (P>0.05) among low (P1-P75) prenatal stress group, adverse associations between maternal blood lead concentrations (log10-transformed) and toddlers' cognitive levels were observed among high (P75-P100) prenatal stress group in the domains of language (β=-33.82, 95%CI: -60.04, -7.59), social behavior (β=-41.00, 95%CI: -63.11, -18.89) and adaptive behavior (β=-17.93, 95%CI: -35.83, -0.03). Prenatal maternal stress may exacerbate the deleterious effects of prenatal exposure to lead on toddler cognitive development. Copyright © 2017 Elsevier B.V. All rights reserved.

Using Ensemble-Based Methods for Directly Estimating Causal Effects: An Investigation of Tree-Based G-Computation

ERIC Educational Resources Information Center

Austin, Peter C.

2012-01-01

Researchers are increasingly using observational or nonrandomized data to estimate causal treatment effects. Essential to the production of high-quality evidence is the ability to reduce or minimize the confounding that frequently occurs in observational studies. When using the potential outcome framework to define causal treatment effects, one…

Why It Is Too Early to Lose Control in Accounts of Item-Specific Proportion Congruency Effects

ERIC Educational Resources Information Center

Bugg, Julie M.; Jacoby, Larry L.; Chanani, Swati

2011-01-01

The item-specific proportion congruency (ISPC) effect is the finding of attenuated interference for mostly incongruent as compared to mostly congruent items. A debate in the Stroop literature concerns the mechanisms underlying this effect. Noting a confound between proportion congruency and contingency, Schmidt and Besner (2008) suggested that…

Evaluating the Cost-Effectiveness of Lifestyle Modification versus Metformin Therapy for the Prevention of Diabetes in Singapore

PubMed Central

Png, May Ee; Yoong, Joanne Su-Yin

2014-01-01

Background In Singapore, as diabetes is an increasingly important public health issue, the cost-effectiveness of pursuing lifestyle modification programs and/or alternative prevention strategies is of critical importance for policymakers. While the US Diabetes Prevention Program (DPP) compared weight loss through lifestyle modification with oral treatment of diabetes drug metformin to prevent/delay the onset of type 2 diabetes in pre-diabetic subjects, no data on either the actual or potential cost effectiveness of such a program is available for East or South-east Asian populations. This study estimates the 3-year cost-effectiveness of lifestyle modification and metformin among pre-diabetic subjects from a Singapore health system and societal perspective. Methodology Cost effectiveness was analysed from 2010–2012 using a decision-based model to estimate the rates of getting diabetes, healthcare costs and health-related quality of life. Cost per quality-adjusted life year (QALY) was estimated using costs relevant to the time horizon of the study from Singapore. All costs are expressed in 2012 US dollars. Principal Findings The total economic cost for non-diabetic subjects from the societal perspective was US$25,867, US$28,108 and US$26,177 for placebo, lifestyle modification and metformin intervention respectively. For diabetic patients, the total economic cost from the societal perspective was US$32,921, US$35,163 and US$33,232 for placebo, lifestyle modification and metformin intervention respectively. Lifestyle modification relative to placebo is likely to be associated with an incremental cost per QALY gained at US$36,663 while that of metformin intervention is likely to be US$6,367 from a societal perspective. Conclusion Based on adaptation of the DPP data to local conditions, both lifestyle modification and metformin intervention are likely to be cost-effective and worth implementing in Singapore to prevent or delay the onset of type 2 diabetes. However, the cost of lifestyle modification from the societal perspective would have to be reduced in order to match the cost-effectiveness of metformin intervention. PMID:25203633

Confounding by dietary pattern of the inverse association between alcohol consumption and type 2 diabetes risk

USDA-ARS?s Scientific Manuscript database

Epidemiology of dietary components and disease risk limits interpretability due to potential residual confounding by correlated dietary components. Dietary pattern analyses by factor analysis or partial least squares may overcome the limitation. To examine confounding by dietary pattern as well as ...

Confounding by dietary patterns of the inverse association between alcohol consumption and type 2 diabetes risk

USDA-ARS?s Scientific Manuscript database

Epidemiology of dietary components and disease risk limits interpretability due to potential residual confounding by correlated dietary components. Dietary pattern analyses by factor analysis or partial least squares may overcome this limitation. To examine confounding by dietary pattern as well as ...

Maternal and Paternal Height and the Risk of Preeclampsia.

PubMed

Lee, Yunsung; Magnus, Per

2018-04-01

The etiology of preeclampsia is unknown. Tall women have been found to have lower incidence of preeclampsia. This points to a possible biological causal effect but may be because of socioeconomic confounding. We used paternal height as an unexposed control to examine confounding. The MoBa (Norwegian Mother and Child Cohort Study) was used to extract data on parental heights, maternal prepregnancy weight, other background factors, and pregnancy outcomes for 99 968 singleton births. Multiple logistic regression was used to estimate odds ratios for preeclampsia according to parental height. The adjusted odds ratio for preeclampsia was 0.74 (95% CI, 0.66-0.82) for women >172 cm as compared with women <164 cm. The adjusted odds ratio for preeclampsia for men >186 cm was 1.03 (95% CI, 0.93-1.15) compared with men <178 cm. The association between maternal height and preeclampsia is unlikely to be because of confounding by familial, socioeconomic factors or by fetal genes related to height. The observed association between maternal height and preeclampsia merits further investigation. © 2018 American Heart Association, Inc.

40 CFR 52.736 - Review of new sources and modifications.

Code of Federal Regulations, 2010 CFR

2010-07-01

... sources and modifications. (a) [Reserved] (b) The rules submitted by the State on March 24, 1988, to... Sources Construction and Modification as effective March 22, 1991. The moratorium on construction and...

Effects of preparation relief and flow channels on seating full coverage castings during cementation.

PubMed

Webb, E L; Murray, H V; Holland, G A; Taylor, D F

1983-06-01

Machined steel dies were used to study the effects of three die modifications on seating full coverage castings during cementation. The die modifications consisted of occlusal channels, occlusal surface relief, and axial channels. Fourteen specimens having one or more forms of die modification were compared with two control specimens having no die modifications. Statistical analysis of the data revealed that the addition of four axial channels to the simulated preparation on the steel die produced a significant reduction in the mean marginal discrepancy during cementation. Occlusal modifications alone failed to produce significant reductions in marginal discrepancies when compared with the control specimens. Occlusal modifications in conjunction with axial channels failed to produce further significant reductions in marginal discrepancies when compared with those reductions observed in specimens having only axial channels.

Residential Modifications and Decline in Physical Function among Community-Dwelling Older Adults

ERIC Educational Resources Information Center

Liu, Sze Y.; Lapane, Kate L.

2009-01-01

Purpose: The purpose of this study is to quantify the effect of residential modification on decreasing risk of physical function decline in 2 years. Design: Cohort study using propensity scores method to control for baseline differences between individuals with residential modifications and those without residential modifications. Participants:…

Effects of Combining Na and Sr additions on Eutectic Modification in Al-Si alloy

NASA Astrophysics Data System (ADS)

Zhu, G. L.; Gu, N. J.; Zhou, B. J.

2017-09-01

Experiments were designed to investigate the effects of strontium and sodium modified on the eutectic silicon for Al-Si alloy. It was found that combining addition of Na and Sr did not appear to cause deleterious interactions of modification, at at the same time, Sr-Na was fairly constant with holding time and without obvious modification fading. Addition of Na-Sr modifier could take effect quickly and decrease incubation period.

Effect modification of the association of cumulative exposure and cancer risk by intensity of exposure and time since exposure cessation: a flexible method applied to cigarette smoking and lung cancer in the SYNERGY Study.

PubMed

Vlaanderen, Jelle; Portengen, Lützen; Schüz, Joachim; Olsson, Ann; Pesch, Beate; Kendzia, Benjamin; Stücker, Isabelle; Guida, Florence; Brüske, Irene; Wichmann, Heinz-Erich; Consonni, Dario; Landi, Maria Teresa; Caporaso, Neil; Siemiatycki, Jack; Merletti, Franco; Mirabelli, Dario; Richiardi, Lorenzo; Gustavsson, Per; Plato, Nils; Jöckel, Karl-Heinz; Ahrens, Wolfgang; Pohlabeln, Hermann; Tardón, Adonina; Zaridze, David; Field, John K; 't Mannetje, Andrea; Pearce, Neil; McLaughlin, John; Demers, Paul; Szeszenia-Dabrowska, Neonila; Lissowska, Jolanta; Rudnai, Peter; Fabianova, Eleonora; Stanescu Dumitru, Rodica; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Boffetta, Paolo; Forastiere, Francesco; Bueno-de-Mesquita, Bas; Peters, Susan; Brüning, Thomas; Kromhout, Hans; Straif, Kurt; Vermeulen, Roel

2014-02-01

The indiscriminate use of the cumulative exposure metric (the product of intensity and duration of exposure) might bias reported associations between exposure to hazardous agents and cancer risk. To assess the independent effects of duration and intensity of exposure on cancer risk, we explored effect modification of the association of cumulative exposure and cancer risk by intensity of exposure. We applied a flexible excess odds ratio model that is linear in cumulative exposure but potentially nonlinear in intensity of exposure to 15 case-control studies of cigarette smoking and lung cancer (1985-2009). Our model accommodated modification of the excess odds ratio per pack-year of cigarette smoking by time since smoking cessation among former smokers. We observed negative effect modification of the association of pack-years of cigarette smoking and lung cancer by intensity of cigarette smoke for persons who smoked more than 20-30 cigarettes per day. Patterns of effect modification were similar across individual studies and across major lung cancer subtypes. We observed strong negative effect modification by time since smoking cessation. Application of our method in this example of cigarette smoking and lung cancer demonstrated that reducing a complex exposure history to a metric such as cumulative exposure is too restrictive.

Effect Modification of the Association of Cumulative Exposure and Cancer Risk by Intensity of Exposure and Time Since Exposure Cessation: A Flexible Method Applied to Cigarette Smoking and Lung Cancer in the SYNERGY Study

PubMed Central

Vlaanderen, Jelle; Portengen, Lützen; Schüz, Joachim; Olsson, Ann; Pesch, Beate; Kendzia, Benjamin; Stücker, Isabelle; Guida, Florence; Brüske, Irene; Wichmann, Heinz-Erich; Consonni, Dario; Landi, Maria Teresa; Caporaso, Neil; Siemiatycki, Jack; Merletti, Franco; Mirabelli, Dario; Richiardi, Lorenzo; Gustavsson, Per; Plato, Nils; Jöckel, Karl-Heinz; Ahrens, Wolfgang; Pohlabeln, Hermann; Tardón, Adonina; Zaridze, David; Field, John K.; 't Mannetje, Andrea; Pearce, Neil; McLaughlin, John; Demers, Paul; Szeszenia-Dabrowska, Neonila; Lissowska, Jolanta; Rudnai, Peter; Fabianova, Eleonora; Stanescu Dumitru, Rodica; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Boffetta, Paolo; Forastiere, Francesco; Bueno-de-Mesquita, Bas; Peters, Susan; Brüning, Thomas; Kromhout, Hans; Straif, Kurt; Vermeulen, Roel

2014-01-01

The indiscriminate use of the cumulative exposure metric (the product of intensity and duration of exposure) might bias reported associations between exposure to hazardous agents and cancer risk. To assess the independent effects of duration and intensity of exposure on cancer risk, we explored effect modification of the association of cumulative exposure and cancer risk by intensity of exposure. We applied a flexible excess odds ratio model that is linear in cumulative exposure but potentially nonlinear in intensity of exposure to 15 case-control studies of cigarette smoking and lung cancer (1985–2009). Our model accommodated modification of the excess odds ratio per pack-year of cigarette smoking by time since smoking cessation among former smokers. We observed negative effect modification of the association of pack-years of cigarette smoking and lung cancer by intensity of cigarette smoke for persons who smoked more than 20–30 cigarettes per day. Patterns of effect modification were similar across individual studies and across major lung cancer subtypes. We observed strong negative effect modification by time since smoking cessation. Application of our method in this example of cigarette smoking and lung cancer demonstrated that reducing a complex exposure history to a metric such as cumulative exposure is too restrictive. PMID:24355332

Gender effects in gaming research: a case for regression residuals?

PubMed

Pfister, Roland

2011-10-01

Numerous recent studies have examined the impact of video gaming on various dependent variables, including the players' affective reactions, positive as well as detrimental cognitive effects, and real-world aggression. These target variables are typically analyzed as a function of game characteristics and player attributes-especially gender. However, findings on the uneven distribution of gaming experience between males and females, on the one hand, and the effect of gaming experience on several target variables, on the other hand, point at a possible confound when gaming experiments are analyzed with a standard analysis of variance. This study uses simulated data to exemplify analysis of regression residuals as a potentially beneficial data analysis strategy for such datasets. As the actual impact of gaming experience on each of the various dependent variables differs, the ultimate benefits of analysis of regression residuals entirely depend on the research question, but it offers a powerful statistical approach to video game research whenever gaming experience is a confounding factor.

Deontic and epistemic reasoning in children revisited: comment on Dack and Astington.

PubMed

Cummins, Denise Dellarosa

2013-11-01

Dack and Astington (Journal of Experimental Child Psychology 110 2011 94-114) attempted to replicate the deontic reasoning advantage among preschoolers reported by Cummins (Memory & Cognition 24 1996 823-829) and by Harris and Nuñez (Child Development. 67 1996 572-1591). Dack and Astington argued that the apparent deontic advantage reported by these studies was in fact an artifact due to a methodological confound, namely, inclusion of an authority in the deontic condition only. Removing this confound attenuated the effect in young children but had no effect on the reasoning of 7-year-olds and adults. Thus, removing reference to authority "explains away" young children's apparent precocity at this type of reasoning. But this explanation rests on (a) a misunderstanding of norms as targets of deontic reasoning and (b) conclusions based on a sample size that was too small to detect the effect in young children. Copyright © 2013 Elsevier Inc. All rights reserved.

Eliminating Survivor Bias in Two-stage Instrumental Variable Estimators.

PubMed

Vansteelandt, Stijn; Walter, Stefan; Tchetgen Tchetgen, Eric

2018-07-01

Mendelian randomization studies commonly focus on elderly populations. This makes the instrumental variables analysis of such studies sensitive to survivor bias, a type of selection bias. A particular concern is that the instrumental variable conditions, even when valid for the source population, may be violated for the selective population of individuals who survive the onset of the study. This is potentially very damaging because Mendelian randomization studies are known to be sensitive to bias due to even minor violations of the instrumental variable conditions. Interestingly, the instrumental variable conditions continue to hold within certain risk sets of individuals who are still alive at a given age when the instrument and unmeasured confounders exert additive effects on the exposure, and moreover, the exposure and unmeasured confounders exert additive effects on the hazard of death. In this article, we will exploit this property to derive a two-stage instrumental variable estimator for the effect of exposure on mortality, which is insulated against the above described selection bias under these additivity assumptions.

The Correlates of Similarity Estimates are Often Misleadingly Positive: The Nature and Scope of the Problem, and Some Solutions

PubMed Central

Wood, Dustin; Furr, R. Michael

2015-01-01

Research on similarity constructs (e.g., dyadic similarity, personality stability; judgment agreement and accuracy) frequently find them to be associated with positive outcomes. However, a methodological pitfall associated with common ‘overall similarity’ indices, which we term the normative-desirability confound (NDC), will regularly result in similarity constructs apparently having more positive effects than they do in reality. In essence, when an individual is estimated to be similar to another person by common indices, this will strongly indicate that the individual has desirable characteristics. Consequently, the correlates of overall similarity indices can often be interpreted as indicating the beneficial effects of having desirable characteristics, without needing to attribute any additional salutary effect to similarity. We show that this confound is present in overall similarity estimates for a wide range of constructs (e.g., personality traits, attitudes, emotions, behaviors, values), how it can be accounted for, and discuss larger implications for our understanding of similarity constructs. PMID:25896284

Why Do White Americans Oppose Race-Targeted Policies? Clarifying the Impact of Symbolic Racism

PubMed Central

Rabinowitz, Joshua L.; Sears, David O.; Sidanius, Jim; Krosnick, Jon A.

2009-01-01

Measures of symbolic racism (SR) have often been used to tap racial prejudice toward Blacks. However, given the wording of questions used for this purpose, some of the apparent effects on attitudes toward policies to help Blacks may instead be due to political conservatism, attitudes toward government, and/or attitudes toward redistributive government policies in general. Using data from national probability sample surveys and an experiment, we explored whether SR has effects even when controlling for these potential confounds and whether its effects are specific to policies involving Blacks. Holding constant conservatism and attitudes toward limited government, SR predicted Whites' opposition to policies designed to help Blacks and more weakly predicted attitudes toward social programs whose beneficiaries were racially ambiguous. An experimental manipulation of policy beneficiaries revealed that SR predicted policy attitudes when Blacks were the beneficiary but not when women were. These findings are consistent with the claim that SR's association with racial policy preferences is not due to these confounds. PMID:20161542

Effects of anesthesia on the cerebral capillary blood flow in young and old mice

NASA Astrophysics Data System (ADS)

Moeini, Mohammad; Tabatabaei, Maryam S.; Bélanger, Samuel; Avti, Pramod; Castonguay, Alexandre; Pouliot, Philippe; Lesage, Frédéric

2015-03-01

Despite recent findings on the possible role of age-related cerebral microvasculature changes in cognition decline, previous studies of capillary blood flow in aging (using animal models) are scarce and limited to anesthetized conditions. Since anesthesia can have different effects in young and old animals, it may introduce a confounding effect in aging studies. The present study aimed to eliminate the potential confound introduced by anesthesia by measuring capillary blood flow parameters in both awake conditions and under isoflurane anesthesia. We used 2-photon laser scanning fluorescence microscopy to measure capillary diameter, red blood cell velocity and flux, hematocrit and capillary volumetric flow in individual capillaries in the barrel cortex of 6- and 24-month old C57Bl/6 mice. It was observed that microvascular properties are significantly affected by anesthesia leading to different trends in capillary blood flow parameters with aging when measured under awake or anesthetized conditions. The findings in this study suggest taking extra care in interpreting aging studies from anesthetized animals.

Confounding of the Association between Radiation Exposure from CT Scans and Risk of Leukemia and Brain Tumors by Cancer Susceptibility Syndromes.

PubMed

Meulepas, Johanna M; Ronckers, Cécile M; Merks, Johannes; Weijerman, Michel E; Lubin, Jay H; Hauptmann, Michael

2016-01-01

Recent studies linking radiation exposure from pediatric computed tomography (CT) to increased risks of leukemia and brain tumors lacked data to control for cancer susceptibility syndromes (CSS). These syndromes might be confounders because they are associated with an increased cancer risk and may increase the likelihood of CT scans performed in children. We identify CSS predisposing to leukemia and brain tumors through a systematic literature search and summarize prevalence and risk estimates. Because there is virtually no empirical evidence in published literature on patterns of CT use for most types of CSS, we estimate confounding bias of relative risks (RR) for categories of radiation exposure based on expert opinion about the current and previous patterns of CT scans among CSS patients. We estimate that radiation-related RRs for leukemia are not meaningfully confounded by Down syndrome, Noonan syndrome, or other CSS. In contrast, RRs for brain tumors may be overestimated due to confounding by tuberous sclerosis complex (TSC) while von Hippel-Lindau disease, neurofibromatosis type 1, or other CSS do not meaningfully confound. Empirical data on the use of CT scans among CSS patients are urgently needed. Our assessment indicates that associations with leukemia reported in previous studies are unlikely to be substantially confounded by unmeasured CSS, whereas brain tumor risks might have been overestimated due to confounding by TSC. Future studies should identify TSC patients in order to avoid overestimation of brain tumor risks due to radiation exposure from CT scans. ©2015 American Association for Cancer Research.

N-acetyltransferase single nucleotide polymorphisms: Emerging concepts serve as a paradigm for understanding complexities of personalized medicine

PubMed Central

Hein, David W.

2009-01-01

Arylamine N-acetyltransferase 1 (NAT1) and 2 (NAT2) exhibit single nucleotide polymorphisms (SNPs) in human populations that modify drug and carcinogen metabolism. This paper updates the identity, location, and functional effects of these SNPs and then follows with emerging concepts for understanding why pharmacogenetic findings may not be replicated consistently. Using this paradigm as an example, laboratory-based mechanistic analyses can reveal complexities such that genetic polymorphisms become biologically and medically relevant when confounding factors are more fully understood and considered. As medical care moves to a more personalized approach, the implications of these confounding factors will be important in understanding the complexities of personalized medicine. PMID:19379125

Cancer biomarker discovery is improved by accounting for variability in general levels of drug sensitivity in pre-clinical models.

PubMed

Geeleher, Paul; Cox, Nancy J; Huang, R Stephanie

2016-09-21

We show that variability in general levels of drug sensitivity in pre-clinical cancer models confounds biomarker discovery. However, using a very large panel of cell lines, each treated with many drugs, we could estimate a general level of sensitivity to all drugs in each cell line. By conditioning on this variable, biomarkers were identified that were more likely to be effective in clinical trials than those identified using a conventional uncorrected approach. We find that differences in general levels of drug sensitivity are driven by biologically relevant processes. We developed a gene expression based method that can be used to correct for this confounder in future studies.

LD Score Regression Distinguishes Confounding from Polygenicity in Genome-Wide Association Studies

PubMed Central

Bulik-Sullivan, Brendan K.; Loh, Po-Ru; Finucane, Hilary; Ripke, Stephan; Yang, Jian; Patterson, Nick; Daly, Mark J.; Price, Alkes L.; Neale, Benjamin M.

2015-01-01

Both polygenicity (i.e., many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of test statistic inflation in many GWAS of large sample size. PMID:25642630

Risk of respiratory and cardiovascular hospitalisation with exposure to bushfire particulates: new evidence from Darwin, Australia.

PubMed

Crabbe, Helen

2012-12-01

The risk of hospitalisation from bushfire exposure events in Darwin, Australia, is examined. Several local studies have found evidence for the effects of exposure to bushfire particulates on respiratory and cardiovascular hospital admissions. They have characterised the risk of admission from seasonal exposures to biomass air pollution. A new, unanalysed data set presented an additional chance to examine unique exposure effects, as there are no anthropogenic sources of particulates in the vicinity of the exposure monitor. The incidence of daily counts of hospital admissions for respiratory and cardiovascular diagnoses was calculated with respect to exposures of particulate matter (PM(10)), course particulate matter, fine particulate matter (FPM) and black carbon composition. A Poisson model was used to calculate unadjusted (crude) measures of effect and then adjusted for known risk factors and confounders. The final model adjusted for the effects of minimum temperature, relative humidity, a smoothed spline for seasonal effects, 'date' for a linear effect over time, day of the week and public and school holidays. A subset analysis adjusted for an influenza epidemic in a particular year. The main findings suggest that respiratory admissions were associated with exposure to PM(10) with a lag of 1 day when adjusted for flu and other confounders (RR = 1.025, 95 % CI 1.000-1.051, p < 0.05). This effect is strongest for exposure to FPM concentrations (RR = 1.091, 95 % CI 1.023-1.163, p < 0.01) when adjusted for flu. Respiratory admissions were also associated with black carbon concentrations recorded the previous day (RR = 1.0004, 95 % CI 1.000-1.0008, p < 0.05), which did not change strength when adjusted for flu. Cardiovascular admissions had the strongest association with exposure to same-day PM and highest RR for exposure to FPM when adjusted for confounders (RR = 1.044, 95 % CI 0.989-1.102). Consistent risks were also found with exposure to black carbon with lags of 0-3 days.

Selection bias and patterns of confounding in cohort studies: the case of the NINFEA web-based birth cohort.

PubMed

Pizzi, Costanza; De Stavola, Bianca L; Pearce, Neil; Lazzarato, Fulvio; Ghiotti, Paola; Merletti, Franco; Richiardi, Lorenzo

2012-11-01

Several studies have examined the effects of sample selection on the exposure-outcome association estimates in cohort studies, but the reasons why this selection may induce bias have not been fully explored. To investigate how sample selection of the web-based NINFEA birth cohort may change the confounding patterns present in the source population. The characteristics of the NINFEA participants (n=1105) were compared with those of the wider source population-the Piedmont Birth Registry (PBR)-(n=36 092), and the association of two exposures (parity and educational level) with two outcomes (low birth weight and birth by caesarean section), while controlling for other risk factors, was studied. Specifically the associations among measured risk factors within each dataset were examined and the exposure-outcome estimates compared in terms of relative ORs. The associations of educational level with the other risk factors (alcohol consumption, folic acid intake, maternal age, pregnancy weight gain, previous miscarriages) partly differed between PBR and NINFEA. This was not observed for parity. Overall, the exposure-outcome estimates derived from NINFEA only differed moderately from those obtained in PBR, with relative ORs ranging between 0.74 and 1.03. Sample selection in cohort studies may alter the confounding patterns originally present in the general population. However, this does not necessarily introduce selection bias in the exposure-outcome estimates, as sample selection may reduce some of the residual confounding present in the general population.

Robust versus consistent variance estimators in marginal structural Cox models.

PubMed

Enders, Dirk; Engel, Susanne; Linder, Roland; Pigeot, Iris

2018-06-11

In survival analyses, inverse-probability-of-treatment (IPT) and inverse-probability-of-censoring (IPC) weighted estimators of parameters in marginal structural Cox models are often used to estimate treatment effects in the presence of time-dependent confounding and censoring. In most applications, a robust variance estimator of the IPT and IPC weighted estimator is calculated leading to conservative confidence intervals. This estimator assumes that the weights are known rather than estimated from the data. Although a consistent estimator of the asymptotic variance of the IPT and IPC weighted estimator is generally available, applications and thus information on the performance of the consistent estimator are lacking. Reasons might be a cumbersome implementation in statistical software, which is further complicated by missing details on the variance formula. In this paper, we therefore provide a detailed derivation of the variance of the asymptotic distribution of the IPT and IPC weighted estimator and explicitly state the necessary terms to calculate a consistent estimator of this variance. We compare the performance of the robust and consistent variance estimators in an application based on routine health care data and in a simulation study. The simulation reveals no substantial differences between the 2 estimators in medium and large data sets with no unmeasured confounding, but the consistent variance estimator performs poorly in small samples or under unmeasured confounding, if the number of confounders is large. We thus conclude that the robust estimator is more appropriate for all practical purposes. Copyright © 2018 John Wiley & Sons, Ltd.

“Skill of Generalized Additive Model to Detect PM2.5 Health ...

EPA Pesticide Factsheets

Summary. Measures of health outcomes are collinear with meteorology and air quality, making analysis of connections between human health and air quality difficult. The purpose of this analysis was to determine time scales and periods shared by the variables of interest (and by implication scales and periods that are not shared). Hospital admissions, meteorology (temperature and relative humidity), and air quality (PM2.5 and daily maximum ozone) for New York City during the period 2000-2006 were decomposed into temporal scales ranging from 2 days to greater than two years using a complex wavelet transform. Health effects were modeled as functions of the wavelet components of meteorology and air quality using the generalized additive model (GAM) framework. This simulation study showed that GAM is extremely successful at extracting and estimating a health effect embedded in a dataset. It also shows that, if the objective in mind is to estimate the health signal but not to fully explain this signal, a simple GAM model with a single confounder (calendar time) whose smooth representation includes a sufficient number of constraints is as good as a more complex model.Introduction. In the context of wavelet regression, confounding occurs when two or more independent variables interact with the dependent variable at the same frequency. Confounding also acts on a variety of time scales, changing the PM2.5 coefficient (magnitude and sign) and its significance ac

On the Confounding Effect of Temperature on Chemical Shift-Encoded Fat Quantification

PubMed Central

Hernando, Diego; Sharma, Samir D.; Kramer, Harald; Reeder, Scott B.

2014-01-01

Purpose To characterize the confounding effect of temperature on chemical shift-encoded (CSE) fat quantification. Methods The proton resonance frequency of water, unlike triglycerides, depends on temperature. This leads to a temperature dependence of the spectral models of fat (relative to water) that are commonly used by CSE-MRI methods. Simulation analysis was performed for 1.5 Tesla CSE fat–water signals at various temperatures and echo time combinations. Oil–water phantoms were constructed and scanned at temperatures between 0 and 40°C using spectroscopy and CSE imaging at three echo time combinations. An explanted human liver, rejected for transplantation due to steatosis, was scanned using spectroscopy and CSE imaging. Fat–water reconstructions were performed using four different techniques: magnitude and complex fitting, with standard or temperature-corrected signal modeling. Results In all experiments, magnitude fitting with standard signal modeling resulted in large fat quantification errors. Errors were largest for echo time combinations near TEinit ≈ 1.3 ms, ΔTE ≈ 2.2 ms. Errors in fat quantification caused by temperature-related frequency shifts were smaller with complex fitting, and were avoided using a temperature-corrected signal model. Conclusion Temperature is a confounding factor for fat quantification. If not accounted for, it can result in large errors in fat quantifications in phantom and ex vivo acquisitions. PMID:24123362

Effects of Multiple Maternal Relationship Transitions on Offspring Antisocial Behavior in Childhood and Adolescence: A Cousin-Comparison Analysis

PubMed Central

Goodnight, Jackson A.; D’Onofrio, Brian M.; Cherlin, Andrew J.; Emery, Robert E.; Van Hulle, Carol A.; Lahey, Benjamin B.

2012-01-01

Previous studies of the association between multiple parental relationship transitions (i.e., when a parent begins or terminates an intimate relationship involving cohabitation) and offspring antisocial behavior have varied in their efforts to rule out confounding influences, such as parental antisocial behavior and low income. They also have been limited in the representativeness of their samples. Thus, it remains unclear to what degree parents’ multiple relationship transitions have independent effects on children’s antisocial behavior. Analyses were conducted using data on 8,652 6–9-year-old, 6,911 10–13-year-old, and 6,495 14-17-year-old offspring of a nationally representative sample of U.S. women. Cousin-comparisons were used in combination with statistical covariates to evaluate the associations between maternal relationship transitions and offspring antisocial behavior in childhood and adolescence. Cousin-comparisons suggested that associations between maternal relationship transitions and antisocial behavior in childhood and early adolescence are largely explained by confounding factors. In contrast, the associations between maternal relationship transitions and offspring delinquency in late adolescence were robust to measured and unmeasured confounds. The present findings suggest that interventions aimed at reducing exposure to parental relationship transitions or addressing the psychosocial consequences of exposure to parental relationship transitions could reduce risk for offspring delinquency in late adolescence. PMID:22829173

Removing the effect of response time on brain activity reveals developmental differences in conflict processing in the posterior medial prefrontal cortex.

PubMed

Carp, Joshua; Fitzgerald, Kate Dimond; Taylor, Stephan F; Weissman, Daniel H

2012-01-02

In functional magnetic resonance imaging (fMRI) studies, researchers often attempt to ensure that group differences in brain activity are not confounded with group differences in mean reaction time (RT). However, even when groups are matched for performance, they may differ in terms of the RT-BOLD relationship: the degree to which brain activity varies with RT on a trial-by-trial basis. Group activation differences might therefore be influenced by group differences in the relationship between brain activity and time on task. Here, we investigated whether correcting for this potential confound alters group differences in brain activity. Specifically, we reanalyzed data from a functional MRI study of response conflict in children and adults, in which conventional analyses indicated that conflict-related activity did not differ between groups. We found that the RT-BOLD relationship was weaker in children than in adults. Consequently, after removing the effect of RT on brain activity, children exhibited greater conflict-related activity than adults in both the posterior medial prefrontal cortex and the right dorsolateral prefrontal cortex. These results identify the RT-BOLD relationship as an important potential confound in fMRI studies of group differences. They also suggest that the magnitude of the RT-BOLD relationship may be a useful biomarker of brain maturity. Copyright © 2011 Elsevier Inc. All rights reserved.