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.

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…

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…

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

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.

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 ...

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.

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

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.

Physical work load and psychological stress of daily activities as predictors of disability pension due to musculoskeletal disorders.

PubMed

Ropponen, Annina; Svedberg, Pia; Koskenvuo, Markku; Silventoinen, Karri; Kaprio, Jaakko

2014-06-01

Physical work loading and psychological stress commonly co-occur in working life, hence potentially having an interrelationship that may affect work incapacity. This prospective cohort study aimed to investigate the effect of stability and change in physical work loading and stress on the risk of disability pension (DP) due to musculoskeletal diagnoses (MSD), while accounting for familial confounding in these associations. Data on 12,455 twins born before 1958 were surveyed of their physical work loading and psychological stress of daily activities in 1975 and 1981. The follow-up data was collected from pension registers until 2004. Cox proportional hazards regression models were used. During the follow up, 893 participants were granted DP due to MSD. Stable high (hazard ratio, HR, 2.21), but also increased physical work loading (HR 2.05) and high psychological stress (HR 2.22) were associated with increased risk for DP, and had significant interaction (p=0.032). The associations were confirmed when accounting for several confounding factors. Stable high but also increased physical work loading and psychological stress of daily activities between two timepoints with 6 years apart confirms their predictive role for an increased risk of DP. Both physical work loading and psychological stress seem to be independent from various confounding factors hence suggesting direct effect on risk for DP providing potential for occupational health care to early identification of persons at risk. © 2014 the Nordic Societies of Public Health.

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

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.

Effects of fire exclusion on forest structure and composition in unlogged ponderosa pine/Douglas-fir forests

Treesearch

Eric G. Keeling; Anna Sala; Thomas H. DeLuca

2006-01-01

Research to date on effects of fire exclusion in ponderosa pine (Pinus ponderosa) forests has been limited by narrow geographical focus, by confounding effects due to prior logging at research sites, and by uncertainty from using reconstructions of past conditions to infer changes. For the work presented here, reference stands in unlogged ponderosa...

Double propensity-score adjustment: A solution to design bias or bias due to incomplete matching.

PubMed

Austin, Peter C

2017-02-01

Propensity-score matching is frequently used to reduce the effects of confounding when using observational data to estimate the effects of treatments. Matching allows one to estimate the average effect of treatment in the treated. Rosenbaum and Rubin coined the term "bias due to incomplete matching" to describe the bias that can occur when some treated subjects are excluded from the matched sample because no appropriate control subject was available. The presence of incomplete matching raises important questions around the generalizability of estimated treatment effects to the entire population of treated subjects. We describe an analytic solution to address the bias due to incomplete matching. Our method is based on using optimal or nearest neighbor matching, rather than caliper matching (which frequently results in the exclusion of some treated subjects). Within the sample matched on the propensity score, covariate adjustment using the propensity score is then employed to impute missing potential outcomes under lack of treatment for each treated subject. Using Monte Carlo simulations, we found that the proposed method resulted in estimates of treatment effect that were essentially unbiased. This method resulted in decreased bias compared to caliper matching alone and compared to either optimal matching or nearest neighbor matching alone. Caliper matching alone resulted in design bias or bias due to incomplete matching, while optimal matching or nearest neighbor matching alone resulted in bias due to residual confounding. The proposed method also tended to result in estimates with decreased mean squared error compared to when caliper matching was used.

Double propensity-score adjustment: A solution to design bias or bias due to incomplete matching

PubMed Central

2016-01-01

Propensity-score matching is frequently used to reduce the effects of confounding when using observational data to estimate the effects of treatments. Matching allows one to estimate the average effect of treatment in the treated. Rosenbaum and Rubin coined the term “bias due to incomplete matching” to describe the bias that can occur when some treated subjects are excluded from the matched sample because no appropriate control subject was available. The presence of incomplete matching raises important questions around the generalizability of estimated treatment effects to the entire population of treated subjects. We describe an analytic solution to address the bias due to incomplete matching. Our method is based on using optimal or nearest neighbor matching, rather than caliper matching (which frequently results in the exclusion of some treated subjects). Within the sample matched on the propensity score, covariate adjustment using the propensity score is then employed to impute missing potential outcomes under lack of treatment for each treated subject. Using Monte Carlo simulations, we found that the proposed method resulted in estimates of treatment effect that were essentially unbiased. This method resulted in decreased bias compared to caliper matching alone and compared to either optimal matching or nearest neighbor matching alone. Caliper matching alone resulted in design bias or bias due to incomplete matching, while optimal matching or nearest neighbor matching alone resulted in bias due to residual confounding. The proposed method also tended to result in estimates with decreased mean squared error compared to when caliper matching was used. PMID:25038071

Caffeine, sleep and wakefulness: implications of new understanding about withdrawal reversal.

PubMed

James, Jack E; Keane, Michael A

2007-12-01

The broad aim of this review is to critically examine the implications of new understanding concerning caffeine withdrawal and withdrawal reversal in the context of research concerned with the effects of caffeine on sleep and wakefulness. A comprehensive search was conducted for relevant experimental studies in the PubMED and PsycINFO databases. Studies were assessed with particular reference to methodological adequacy for controlling against confounding due to caffeine withdrawal and withdrawal reversal. This assessment was used to clarify evidence of effects, highlight areas of ambiguity and derive recommendations for future research. It was found that researchers have generally failed to take account of the fact that habitual use of caffeine, even at moderate levels, leads to physical dependence evidenced by physiological, behavioural and subjective withdrawal effects during periods of abstinence. Consequently, there has been near-complete absence of adequate methodological controls against confounding due to reversal of withdrawal effects when caffeine is experimentally administered. The findings of what has been a substantial research effort to elucidate the effects of caffeine on sleep and wakefulness, undertaken over a period spanning decades, are ambiguous. Current shortcomings can be redressed by incorporating suitable controls in new experimental designs.

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.

Work-Home Interference, Perceived Total Workload, and the Risk of Future Sickness Absence Due to Stress-Related Mental Diagnoses Among Women and Men: a Prospective Twin Study.

PubMed

Svedberg, Pia; Mather, Lisa; Bergström, Gunnar; Lindfors, Petra; Blom, Victoria

2018-02-01

Work-home interference has been proposed as an important explanation for sickness absence (SA). Previous studies show mixed results, have not accounted for familial factors (genetics and shared everyday environment), or investigated diagnosis specific SA. The aim was to study whether work-home interference and perceived total workload predict SA due to stress-related mental diagnoses, or SA due to other mental diagnoses, among women and men, when adjusting for various confounders and familial factors. This study included 11,916 twins, 19-47 years (49% women). Data on work-to-home and home-to-work conflicts, perceived total workload, and relevant confounders were derived from a 2005 survey, and national register data on SA spells until 2013 were obtained. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Discordant twin pair design was applied to adjust for familial factors. Each one unit increase in work-to-home and home-to-work conflicts, and perceived total workload was associated with higher odds for SA due to stress-related mental diagnoses and to SA due to other mental diagnoses among women, when adjusting for sociodemographic factors (ORs 1.15-1.31). Including health or familial factors, no associations remained. For men, each one unit increase in work-to-home conflicts was associated with higher odds for SA due to stress-related diagnoses (ORs 1.23-1.35), independently of confounders. Work-to-home conflict was independently associated with future SA due to stress-related diagnoses among men only. Health- and work-related factors seem to be important confounders when researching work-home interference, perceived total workload, and SA. Not including such confounders involves risking drawing incorrect conclusions. Further studies are needed to confirm sex differences and whether genetic factors are important for the associations studied.

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

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.

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.

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.

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.

Diversity of gastrointestinal helminths in Dall's sheep and the negative association of the abomasal nematode, Marshallagia marshalli, with fitness indicators

USDA-ARS?s Scientific Manuscript database

Gastrointestinal helminths can have a detrimental effect on the fitness of wild ungulates. Arctic and Subarctic ecosystems are ideal for the study of host-parasite interactions due to the comparatively simple ecological interactions and limited confounding factors. We used a unique dataset collected...

Is Self-Regulation "All in the Family"? Testing Environmental Effects Using Within-Family Quasi-Experiments

ERIC Educational Resources Information Center

Deater-Deckard, Kirby

2016-01-01

Most of the individual difference variance in the population is found "within" families, yet studying the processes causing this variation is difficult due to confounds between genetic and nongenetic influences. Quasi-experiments can be used to test hypotheses regarding environment exposure (e.g., timing, duration) while controlling for…

Adolescent Substance Use, Sleep, and Academic Achievement: Evidence of Harm Due to Caffeine

ERIC Educational Resources Information Center

James, Jack E.; Kristjansson, Alfgeir Logi; Sigfusdottir, Inga Dora

2011-01-01

Using academic achievement as the key outcome variable, 7377 Icelandic adolescents were surveyed for cigarette smoking, alcohol use, daytime sleepiness, caffeine use, and potential confounders. Structural equation modeling (SEM) was used to examine direct and indirect effects of measured and latent variables in two models: the first with caffeine…

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.

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.

Is the association between posttraumatic stress disorder symptoms and poor health due to a common familial or genetic factor?

PubMed Central

Roy-Byrne, Peter P.; Noonan, Carolyn; Afari, Niloofar; Buchwald, Dedra; Goldberg, Jack

2010-01-01

Objective The objective of this study was to identify genetic, familial and environmental contributions to the association between posttraumatic stress disorder (PTSD) symptoms and poor health. Methods A community sample of 1852 twin pairs was assessed for symptoms of PTSD [with the Impact of Events Scale (IES)] and self-reported global health status using a single five-level question. An ordinal logistic regression model estimated odds ratio/s (OR) for the association between PTSD and health status. Within-pair analysis assessed confounding by familial and genetic factors and adjusted for the possible confounding influence of age, sex, race, education and self-reported physician diagnosis of depression. Results The IES was strongly and significantly associated with self-reported health [OR = 1.8; 95% confidence interval (95% CI) = 1.5–2.2; highest quartile vs. lowest quartile]. This association remained significant in within-pair analysis (OR = 1.3; 95% CI=1.0–1.7), but after further adjustment for sociodemographics and depression, it was no longer significant (Ptrend=.17). Separate analysis by zygosity did not show differential effect in monozygotic or dizygotic pairs. Conclusion These findings suggest that the association between PTSD symptoms and poor health is, in part, due to familial confounding and sociodemographic factors. Little evidence of confounding by genetic factors was found. These findings suggest that early prevention efforts would have the greatest potential for improving poor health in PTSD-prone patients, whereas later intervention efforts directed at treating PTSD may have a more limited impact on improving poor health. PMID:16950376

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.

Stability and change of body mass index as a predictor of disability pension.

PubMed

Ropponen, Annina; Silventoinen, Karri; Koskenvuo, Markku; Svedberg, Pia; Kaprio, Jaakko

2016-06-01

To investigate whether stability or change in body mass index (BMI) predict disability pension (DP) due to musculoskeletal diagnosis (MSD) when controlling for familial confounding. Our study cohort consisted of 17,169 Finnish twins born before 1958. Data on BMI and multiple covariates from questionnaires in 1975 and 1981 were included and DPs were collected from the national pension registers until the end of 2004. Cox proportional hazards regression models with Hazard Ratios (HR) and 95% Confidence Intervals (CI) were used for statistical analyses. General DP was granted to 2853 individuals and DP due to MSD to 1143 individuals during the 23-year follow-up. A one-unit increase in BMI in both 1975 (HR 1.08, 95% CI 1.05, 1.10) and 1981 (HR 1.06, 95% CI 1.04, 1.07), as well as the stability of and change in BMI from 1975 to 1981 were all associated with an increased risk of DP. These associations held in the analyses controlling for multiple covariates (age, sex, socioeconomic status, education, marital status, leisure-time physical activity, and musculoskeletal pain), and mainly also familial confounding, that is, genetics and shared environment. HR for stable obesity was 2.28 (95% CI 1.69, 3.08) for DP due to MSD, and 1.91 (95% CI 1.56, 2.34) for general DP in the fully adjusted models. CONCLUSIONS BMI IS AN EARLY PREDICTOR OF GENERAL DP AND ALSO OF DP DUE TO MSD OWING TO THE INDEPENDENCY OF VARIOUS COVARIATES AND POTENTIALLY ALSO FAMILIAL CONFOUNDING, BMI MAY POSSIBLY HAVE A DIRECT EFFECT ON THE RISK OF DP. © 2016 the Nordic Societies of Public Health.

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.

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.

Generalizability of 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 ...

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.

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 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

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/

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.

Homophily and Contagion Are Generically Confounded in Observational Social Network Studies

PubMed Central

Shalizi, Cosma Rohilla; Thomas, Andrew C.

2012-01-01

The authors consider processes on social networks that can potentially involve three factors: homophily, or the formation of social ties due to matching individual traits; social contagion, also known as social influence; and the causal effect of an individual’s covariates on his or her behavior or other measurable responses. The authors show that generically, all of these are confounded with each other. Distinguishing them from one another requires strong assumptions on the parametrization of the social process or on the adequacy of the covariates used (or both). In particular the authors demonstrate, with simple examples, that asymmetries in regression coefficients cannot identify causal effects and that very simple models of imitation (a form of social contagion) can produce substantial correlations between an individual’s enduring traits and his or her choices, even when there is no intrinsic affinity between them. The authors also suggest some possible constructive responses to these results. PMID:22523436

Why does early sexual intercourse predict subsequent maladjustment? Exploring potential familial confounds.

PubMed

Donahue, Kelly L; Lichtenstein, Paul; Långström, Niklas; D'Onofrio, Brian M

2013-02-01

Previous studies have found an association between early age at first sexual intercourse and subsequent psychosocial maladjustment. Using a quasi-experimental approach, we examined the extent to which this observed association may be due to familial confounds not explored in prior research. Using a population-based cohort of Swedish adult twins (ages 19-47; N = 12,126), we examined the nature of the association between early sexual intercourse (i.e., first intercourse occurring before age 16) and various outcomes reflecting psychosocial health, including substance use, depression, criminal convictions, and adolescent childbearing. We used two methods--discordant-twin analyses and bivariate twin modeling--to estimate the extent to which genetic and environmental confounds explained observed associations. Individuals who engaged in early intercourse were at greater risk for most of the adverse psychosocial health outcomes measured in this study. However, twin pairs discordant for engaging in early intercourse did not differ significantly in their risk for psychosocial maladjustment. Our results indicated that early age at first sexual intercourse and subsequent psychosocial maladjustment may be associated because of familial factors shared by twins. Early intercourse may be associated with poor psychosocial health largely due to shared familial influences rather than through a direct causal connection. Therefore, effective and efficient interventions should address other risk factors common to early intercourse and poor psychosocial health.

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.

Individual tree differences confound effects of growth regulators in rooting sugar maple softwood cuttings

Treesearch

John R. Donnelly

1971-01-01

Softwood stem cuttings from three mature sugar maple trees were treated with several types and concentrations of growth regulators. Lack of statistical significance was due to extreme variability in tree response: low levels of auxin stimulated rooting in two study trees, while auxins inhibited rooting in the other tree. It is postulated that variations in rooting...

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.

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

Do nonphysical punishments reduce antisocial behavior more than spanking? a comparison using the strongest previous causal evidence against spanking

PubMed Central

2010-01-01

Background The strongest causal evidence that customary spanking increases antisocial behavior is based on prospective studies that control statistically for initial antisocial differences. None of those studies have investigated alternative disciplinary tactics that parents could use instead of spanking, however. Further, the small effects in those studies could be artifactual due to residual confounding, reflecting child effects on the frequency of all disciplinary tactics. This study re-analyzes the strongest causal evidence against customary spanking and uses these same methods to determine whether alternative disciplinary tactics are more effective in reducing antisocial behavior. Methods This study re-analyzed a study by Straus et al.[1] on spanking and antisocial behavior using a sample of 785 children who were 6 to 9 years old in the 1988 cohort of the American National Longitudinal Survey of Youth. The comprehensiveness and reliability of the covariate measure of initial antisocial behavior were varied to test for residual confounding. All analyses were repeated for grounding, privilege removal, and sending children to their room, and for psychotherapy. To account for covarying use of disciplinary tactics, the analyses were redone first for the 73% who had reported using at least one discipline tactic and second by controlling for usage of other disciplinary tactics and psychotherapy. Results The apparently adverse effect of spanking on antisocial behavior was replicated using the original trichotomous covariate for initial antisocial behavior. A similar pattern of adverse effects was shown for grounding and psychotherapy and partially for the other two disciplinary tactics. All of these effects became non-significant after controlling for latent comprehensive measures of externalizing behavior problems. Conclusions These results are consistent with residual confounding, a statistical artifact that makes all corrective actions by parents and psychologists appear to increase children's antisocial behavior due to child effects on parents. Improved research methods are needed to discriminate between effective vs. counterproductive implementations of disciplinary tactics. How and when disciplinary tactics are used may be more important than which type of tactic is used. PMID:20175902

Do nonphysical punishments reduce antisocial behavior more than spanking? a comparison using the strongest previous causal evidence against spanking.

PubMed

Larzelere, Robert E; Cox, Ronald B; Smith, Gail L

2010-02-22

The strongest causal evidence that customary spanking increases antisocial behavior is based on prospective studies that control statistically for initial antisocial differences. None of those studies have investigated alternative disciplinary tactics that parents could use instead of spanking, however. Further, the small effects in those studies could be artifactual due to residual confounding, reflecting child effects on the frequency of all disciplinary tactics. This study re-analyzes the strongest causal evidence against customary spanking and uses these same methods to determine whether alternative disciplinary tactics are more effective in reducing antisocial behavior. This study re-analyzed a study by Straus et al.1 on spanking and antisocial behavior using a sample of 785 children who were 6 to 9 years old in the 1988 cohort of the American National Longitudinal Survey of Youth. The comprehensiveness and reliability of the covariate measure of initial antisocial behavior were varied to test for residual confounding. All analyses were repeated for grounding, privilege removal, and sending children to their room, and for psychotherapy. To account for covarying use of disciplinary tactics, the analyses were redone first for the 73% who had reported using at least one discipline tactic and second by controlling for usage of other disciplinary tactics and psychotherapy. The apparently adverse effect of spanking on antisocial behavior was replicated using the original trichotomous covariate for initial antisocial behavior. A similar pattern of adverse effects was shown for grounding and psychotherapy and partially for the other two disciplinary tactics. All of these effects became non-significant after controlling for latent comprehensive measures of externalizing behavior problems. These results are consistent with residual confounding, a statistical artifact that makes all corrective actions by parents and psychologists appear to increase children's antisocial behavior due to child effects on parents. Improved research methods are needed to discriminate between effective vs. counterproductive implementations of disciplinary tactics. How and when disciplinary tactics are used may be more important than which type of tactic is used.

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.

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

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.

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.

Assessing the impact of nano- and micro-scale zerovalent iron particles on soil microbial activities: particle reactivity interferes with assay conditions and interpretation of genuine microbial effects.

PubMed

Cullen, Laurence G; Tilston, Emma L; Mitchell, Geoff R; Collins, Chris D; Shaw, Liz J

2011-03-01

The effects of nano-scale and micro-scale zerovalent iron (nZVI and mZVI) particles on general (dehydrogenase and hydrolase) and specific (ammonia oxidation potential, AOP) activities mediated by the microbial community in an uncontaminated soil were examined. nZVI (diameter 12.5 nm; 10 mg g⁻¹ soil) apparently inhibited AOP and nZVI and mZVI apparently stimulated dehydrogenase activity but had minimal influence on hydrolase activity. Sterile experiments revealed that the apparent inhibition of AOP could not be interpreted as such due to the confounding action of the particles, whereas, the nZVI-enhanced dehydrogenase activity could represent the genuine response of a stimulated microbial population or an artifact of ZVI reactivity. Overall, there was no evidence for negative effects of nZVI or mZVI on the processes studied. When examining the impact of redox active particles such as ZVI on microbial oxidation-reduction reactions, potential confounding effects of the test particles on assay conditions should be considered. Copyright © 2010 Elsevier Ltd. All rights reserved.

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.

Interpretational Confounding Is Due to Misspecification, Not to Type of Indicator: Comment on Howell, Breivik, and Wilcox (2007)

ERIC Educational Resources Information Center

Bollen, Kenneth A.

2007-01-01

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…

phMRI: methodological considerations for mitigating potential confounding factors

PubMed Central

Bourke, Julius H.; Wall, Matthew B.

2015-01-01

Pharmacological Magnetic Resonance Imaging (phMRI) is a variant of conventional MRI that adds pharmacological manipulations in order to study the effects of drugs, or uses pharmacological probes to investigate basic or applied (e.g., clinical) neuroscience questions. Issues that may confound the interpretation of results from various types of phMRI studies are briefly discussed, and a set of methodological strategies that can mitigate these problems are described. These include strategies that can be employed at every stage of investigation, from study design to interpretation of resulting data, and additional techniques suited for use with clinical populations are also featured. Pharmacological MRI is a challenging area of research that has both significant advantages and formidable difficulties, however with due consideration and use of these strategies many of the key obstacles can be overcome. PMID:25999812

Five Steps to Successfully Implement and Evaluate Propensity Score Matching in Clinical Research Studies.

PubMed

Staffa, Steven J; Zurakowski, David

2018-01-09

In clinical research, the gold standard level of evidence is the randomized controlled trial (RCT). The availability of nonrandomized retrospective data is growing; however, a primary concern of analyzing such data is comparability of the treatment groups with respect to confounding variables. Propensity score matching (PSM) aims to equate treatment groups with respect to measured baseline covariates to achieve a comparison with reduced selection bias. It is a valuable statistical methodology that mimics the RCT, and it may create an "apples to apples" comparison while reducing bias due to confounding. PSM can improve the quality of anesthesia research and broaden the range of research opportunities. PSM is not necessarily a magic bullet for poor-quality data, but rather may allow the researcher to achieve balanced treatment groups similar to a RCT when high-quality observational data are available. PSM may be more appealing than the common approach of including confounders in a regression model because it allows for a more intuitive analysis of a treatment effect between 2 comparable groups.We present 5 steps that anesthesiologists can use to successfully implement PSM in their research with an example from the 2015 Pediatric National Surgical Quality Improvement Program: a validated, annually updated surgery and anesthesia pediatric database. The first step of PSM is to identify its feasibility with regard to the data at hand and ensure availability of data on any potential confounders. The second step is to obtain the set of propensity scores from a logistic regression model with treatment group as the outcome and the balancing factors as predictors. The third step is to match patients in the 2 treatment groups with similar propensity scores, balancing all factors. The fourth step is to assess the success of the matching with balance diagnostics, graphically or analytically. The fifth step is to apply appropriate statistical methodology using the propensity-matched data to compare outcomes among treatment groups.PSM is becoming an increasingly more popular statistical methodology in medical research. It often allows for improved evaluation of a treatment effect that may otherwise be invalid due to a lack of balance between the 2 treatment groups with regard to confounding variables. PSM may increase the level of evidence of a study and in turn increases the strength and generalizability of its results. Our step-by-step approach provides a useful strategy for anesthesiologists to implement PSM in their future research.

Naming and categorizing objects: task differences modulate the polarity of semantic effects in the picture-word interference paradigm.

PubMed

Hantsch, Ansgar; Jescheniak, Jörg D; Mädebach, Andreas

2012-07-01

The picture-word interference paradigm is a prominent tool for studying lexical retrieval during speech production. When participants name the pictures, interference from semantically related distractor words has regularly been shown. By contrast, when participants categorize the pictures, facilitation from semantically related distractors has typically been found. In the extant studies, however, differences in the task instructions (naming vs. categorizing) were confounded with the response level: While responses in naming were typically located at the basic level (e.g., "dog"), responses were located at the superordinate level in categorization (e.g., "animal"). The present study avoided this confound by having participants respond at the basic level in both naming and categorization, using the same pictures, distractors, and verbal responses. Our findings confirm the polarity reversal of the semantic effects--that is, semantic interference in naming, and semantic facilitation in categorization. These findings show that the polarity reversal of the semantic effect is indeed due to the different tasks and is not an artifact of the different response levels used in previous studies. Implications for current models of language production are discussed.

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.

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.

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.

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

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

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.

A propensity score approach to correction for bias due to population stratification using genetic and non-genetic factors.

PubMed

Zhao, Huaqing; Rebbeck, Timothy R; Mitra, Nandita

2009-12-01

Confounding due to population stratification (PS) arises when differences in both allele and disease frequencies exist in a population of mixed racial/ethnic subpopulations. Genomic control, structured association, principal components analysis (PCA), and multidimensional scaling (MDS) approaches have been proposed to address this bias using genetic markers. However, confounding due to PS can also be due to non-genetic factors. Propensity scores are widely used to address confounding in observational studies but have not been adapted to deal with PS in genetic association studies. We propose a genomic propensity score (GPS) approach to correct for bias due to PS that considers both genetic and non-genetic factors. We compare the GPS method with PCA and MDS using simulation studies. Our results show that GPS can adequately adjust and consistently correct for bias due to PS. Under no/mild, moderate, and severe PS, GPS yielded estimated with bias close to 0 (mean=-0.0044, standard error=0.0087). Under moderate or severe PS, the GPS method consistently outperforms the PCA method in terms of bias, coverage probability (CP), and type I error. Under moderate PS, the GPS method consistently outperforms the MDS method in terms of CP. PCA maintains relatively high power compared to both MDS and GPS methods under the simulated situations. GPS and MDS are comparable in terms of statistical properties such as bias, type I error, and power. The GPS method provides a novel and robust tool for obtaining less-biased estimates of genetic associations that can consider both genetic and non-genetic factors. 2009 Wiley-Liss, Inc.

Beyond total treatment effects in randomised controlled trials: Baseline measurement of intermediate outcomes needed to reduce confounding in mediation investigations.

PubMed

Landau, Sabine; Emsley, Richard; Dunn, Graham

2018-06-01

Random allocation avoids confounding bias when estimating the average treatment effect. For continuous outcomes measured at post-treatment as well as prior to randomisation (baseline), analyses based on (A) post-treatment outcome alone, (B) change scores over the treatment phase or (C) conditioning on baseline values (analysis of covariance) provide unbiased estimators of the average treatment effect. The decision to include baseline values of the clinical outcome in the analysis is based on precision arguments, with analysis of covariance known to be most precise. Investigators increasingly carry out explanatory analyses to decompose total treatment effects into components that are mediated by an intermediate continuous outcome and a non-mediated part. Traditional mediation analysis might be performed based on (A) post-treatment values of the intermediate and clinical outcomes alone, (B) respective change scores or (C) conditioning on baseline measures of both intermediate and clinical outcomes. Using causal diagrams and Monte Carlo simulation, we investigated the performance of the three competing mediation approaches. We considered a data generating model that included three possible confounding processes involving baseline variables: The first two processes modelled baseline measures of the clinical variable or the intermediate variable as common causes of post-treatment measures of these two variables. The third process allowed the two baseline variables themselves to be correlated due to past common causes. We compared the analysis models implied by the competing mediation approaches with this data generating model to hypothesise likely biases in estimators, and tested these in a simulation study. We applied the methods to a randomised trial of pragmatic rehabilitation in patients with chronic fatigue syndrome, which examined the role of limiting activities as a mediator. Estimates of causal mediation effects derived by approach (A) will be biased if one of the three processes involving baseline measures of intermediate or clinical outcomes is operating. Necessary assumptions for the change score approach (B) to provide unbiased estimates under either process include the independence of baseline measures and change scores of the intermediate variable. Finally, estimates provided by the analysis of covariance approach (C) were found to be unbiased under all the three processes considered here. When applied to the example, there was evidence of mediation under all methods but the estimate of the indirect effect depended on the approach used with the proportion mediated varying from 57% to 86%. Trialists planning mediation analyses should measure baseline values of putative mediators as well as of continuous clinical outcomes. An analysis of covariance approach is recommended to avoid potential biases due to confounding processes involving baseline measures of intermediate or clinical outcomes, and not simply for increased precision.

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.

Smoking and early retirement due to chronic disability.

PubMed

Bengtsson, Tommy; Nilsson, Anton

2018-05-01

This paper considers the long-term effects of smoking on disability retirement in Sweden. Smoking is known to have damaging effects on health, but there is limited evidence on how the effects of smoking translate into worse labour market outcomes, such as the inability to work. In contrast to the few previous studies on smoking and disability retirement, we use a large population sample with registry information on smoking, which is recorded for all women who give birth in Sweden. Thanks to these comprehensive data, we are able to account for a much broader range of potential confounders. In particular, by the use of sibling and twin fixed effects, we account for unobserved heterogeneity in childhood environment and family characteristics. Given that smoking is often initiated in adolescence, one would suspect such factors to play important roles. Among individuals aged 50-64 in 2011, a simple model suggested smokers to have a 5 percentage point higher probability of receiving (full) disability pension, making them more than twice as likely as non-smokers to receive this. However, in a model with sibling fixed effects, the size of the effect was reduced by more than a third. The results point to the importance of confounders, such as childhood circumstances or behaviours, which were not accounted for by previous studies. We also consider effects on disability due to different health conditions. In relative terms, effects are the largest for circulatory conditions and tumours. Results are largely driven by health problems severe enough to merit hospitalization, and there is no evidence of a role played by financial incentives. Copyright © 2018 Elsevier B.V. All rights reserved.

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.

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.

Testing concordance of instrumental variable effects in generalized linear models with application to Mendelian randomization

PubMed Central

Dai, James Y.; Chan, Kwun Chuen Gary; Hsu, Li

2014-01-01

Instrumental variable regression is one way to overcome unmeasured confounding and estimate causal effect in observational studies. Built on structural mean models, there has been considerale work recently developed for consistent estimation of causal relative risk and causal odds ratio. Such models can sometimes suffer from identification issues for weak instruments. This hampered the applicability of Mendelian randomization analysis in genetic epidemiology. When there are multiple genetic variants available as instrumental variables, and causal effect is defined in a generalized linear model in the presence of unmeasured confounders, we propose to test concordance between instrumental variable effects on the intermediate exposure and instrumental variable effects on the disease outcome, as a means to test the causal effect. We show that a class of generalized least squares estimators provide valid and consistent tests of causality. For causal effect of a continuous exposure on a dichotomous outcome in logistic models, the proposed estimators are shown to be asymptotically conservative. When the disease outcome is rare, such estimators are consistent due to the log-linear approximation of the logistic function. Optimality of such estimators relative to the well-known two-stage least squares estimator and the double-logistic structural mean model is further discussed. PMID:24863158

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.

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.

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

Study design and data analysis considerations for the discovery of prognostic molecular biomarkers: a case study of progression free survival in advanced serous ovarian cancer.

PubMed

Qin, Li-Xuan; Levine, Douglas A

2016-06-10

Accurate discovery of molecular biomarkers that are prognostic of a clinical outcome is an important yet challenging task, partly due to the combination of the typically weak genomic signal for a clinical outcome and the frequently strong noise due to microarray handling effects. Effective strategies to resolve this challenge are in dire need. We set out to assess the use of careful study design and data normalization for the discovery of prognostic molecular biomarkers. Taking progression free survival in advanced serous ovarian cancer as an example, we conducted empirical analysis on two sets of microRNA arrays for the same set of tumor samples: arrays in one set were collected using careful study design (that is, uniform handling and randomized array-to-sample assignment) and arrays in the other set were not. We found that (1) handling effects can confound the clinical outcome under study as a result of chance even with randomization, (2) the level of confounding handling effects can be reduced by data normalization, and (3) good study design cannot be replaced by post-hoc normalization. In addition, we provided a practical approach to define positive and negative control markers for detecting handling effects and assessing the performance of a normalization method. Our work showcased the difficulty of finding prognostic biomarkers for a clinical outcome of weak genomic signals, illustrated the benefits of careful study design and data normalization, and provided a practical approach to identify handling effects and select a beneficial normalization method. Our work calls for careful study design and data analysis for the discovery of robust and translatable molecular biomarkers.

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.

Shared processing in multiple object tracking and visual working memory in the absence of response order and task order confounds

PubMed Central

Howe, Piers D. L.

2017-01-01

To understand how the visual system represents multiple moving objects and how those representations contribute to tracking, it is essential that we understand how the processes of attention and working memory interact. In the work described here we present an investigation of that interaction via a series of tracking and working memory dual-task experiments. Previously, it has been argued that tracking is resistant to disruption by a concurrent working memory task and that any apparent disruption is in fact due to observers making a response to the working memory task, rather than due to competition for shared resources. Contrary to this, in our experiments we find that when task order and response order confounds are avoided, all participants show a similar decrease in both tracking and working memory performance. However, if task and response order confounds are not adequately controlled for we find substantial individual differences, which could explain the previous conflicting reports on this topic. Our results provide clear evidence that tracking and working memory tasks share processing resources. PMID:28410383

Shared processing in multiple object tracking and visual working memory in the absence of response order and task order confounds.

PubMed

Lapierre, Mark D; Cropper, Simon J; Howe, Piers D L

2017-01-01

To understand how the visual system represents multiple moving objects and how those representations contribute to tracking, it is essential that we understand how the processes of attention and working memory interact. In the work described here we present an investigation of that interaction via a series of tracking and working memory dual-task experiments. Previously, it has been argued that tracking is resistant to disruption by a concurrent working memory task and that any apparent disruption is in fact due to observers making a response to the working memory task, rather than due to competition for shared resources. Contrary to this, in our experiments we find that when task order and response order confounds are avoided, all participants show a similar decrease in both tracking and working memory performance. However, if task and response order confounds are not adequately controlled for we find substantial individual differences, which could explain the previous conflicting reports on this topic. Our results provide clear evidence that tracking and working memory tasks share processing resources.

Gateway Effects: Why the Cited Evidence Does Not Support Their Existence for Low-Risk Tobacco Products (and What Evidence Would).

PubMed

Phillips, Carl V

2015-05-21

It is often claimed that low-risk drugs still create harm because of "gateway effects", in which they cause the use of a high-risk alternative. Such claims are popular among opponents of tobacco harm reduction, claiming that low-risk tobacco products (e.g., e-cigarettes, smokeless tobacco) cause people to start smoking, sometimes backed by empirical studies that ostensibly support the claim. However, these studies consistently ignore the obvious alternative causal pathways, particularly that observed associations might represent causation in the opposite direction (smoking causes people to seek low-risk alternatives) or confounding (the same individual characteristics increase the chance of using any tobacco product). Due to these complications, any useful analysis must deal with simultaneity and confounding by common cause. In practice, existing analyses seem almost as if they were designed to provide teaching examples about drawing simplistic and unsupported causal conclusions from observed associations. The present analysis examines what evidence and research strategies would be needed to empirically detect such a gateway effect, if there were one, explaining key methodological concepts including causation and confounding, examining the logic of the claim, identifying potentially useful data, and debunking common fallacies on both sides of the argument, as well as presenting an extended example of proper empirical testing. The analysis demonstrates that none of the empirical studies to date that are purported to show a gateway effect from tobacco harm reduction products actually does so. The observations and approaches can be generalized to other cases where observed association of individual characteristics in cross-sectional data could result from any of several causal relationships.

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.

Forest species diversity reduces disease risk in a generalist plant pathogen invasion

USGS Publications Warehouse

Haas, Sarah E.; Hooten, Mevin B.; Rizzo, David M.; Meentemeyer, Ross K.

2011-01-01

Empirical evidence suggests that biodiversity loss can increase disease transmission, yet our understanding of the 'diversity-disease hypothesis' for generalist pathogens in natural ecosystems is limited. We used a landscape epidemiological approach to examine two scenarios regarding diversity effects on the emerging plant pathogen Phytophthora ramorum across a broad, heterogeneous ecoregion: (1) an amplification effect exists where disease risk is greater in areas with higher plant diversity due to the pathogen's wide host range, or (2) a dilution effect where risk is reduced with increasing diversity due to lower competency of alternative hosts. We found evidence for pathogen dilution, whereby disease risk was lower in sites with higher species diversity, after accounting for potentially confounding effects of host density and landscape heterogeneity. Our results suggest that although nearly all plants in the ecosystem are hosts, alternative hosts may dilute disease transmission by competent hosts, thereby buffering forest health from infectious disease.

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.

In plastico: laboratory material newness affects growth and reproduction of Daphnia magna reared in 50-ml polypropylene tubes

PubMed Central

Cuhra, Marek; Bøhn, Thomas; Cuhra, Petr

2017-01-01

Plastic laboratory materials are found to affect vital parameters of the waterflea Daphnia magna. The main responsible factor is defined as “newness” of the materials. Juvenile D. magna were raised individually in; a) new laboratory-standard 50 ml polypropylene tubes, and; b) identical tubes which had been washed and aerated for several weeks. Newness had significant effects on growth and fecundity of D. magna. New tubes caused delayed maturation, reduced reproduction and reduced growth when compared to washed and re-used tubes of the same commercial brand. The findings indicate that newness of tubes has inhibiting or toxic effects on D. magna. Often laboratory plastics are intended for single-use due to sterility demands. Newness might be an important confounding factor in research results and should not be disregarded. Disposable plastic utensils may come with a seemingly ignored cost and induce adverse effects in biological test-organisms and systems. The presented findings accentuate continued need for general awareness concerning confounding factors stemming from material laboratory environment. Based on the present findings the authors suggest that plastics intended for use in sensitive research may need to be washed and aerated prior to use. PMID:28425469

Solar radiation increases suicide rate after adjusting for other climate factors in South Korea.

PubMed

Jee, Hee-Jung; Cho, Chul-Hyun; Lee, Yu Jin; Choi, Nari; An, Hyonggin; Lee, Heon-Jeong

2017-03-01

Previous studies have indicated that suicide rates have significant seasonal variations. There is seasonal discordance between temperature and solar radiation due to the monsoon season in South Korea. We investigated the seasonality of suicide and assessed its association with climate variables in South Korea. Suicide rates were obtained from the National Statistical Office of South Korea, and climatic data were obtained from the Korea Meteorological Administration for the period of 1992-2010. We conducted analyses using a generalized additive model (GAM). First, we explored the seasonality of suicide and climate variables such as mean temperature, daily temperature range, solar radiation, and relative humidity. Next, we identified confounding climate variables associated with suicide rate. To estimate the adjusted effect of solar radiation on the suicide rate, we investigated the confounding variables using a multivariable GAM. Suicide rate showed seasonality with a pattern similar to that of solar radiation. We found that the suicide rate increased 1.008 times when solar radiation increased by 1 MJ/m 2 after adjusting for other confounding climate factors (P < 0.001). Solar radiation has a significant linear relationship with suicide after adjusting for region, other climate variables, and time trends. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Pot binding as a variable confounding plant phenotype: theoretical derivation and experimental observations.

PubMed

Sinclair, Thomas R; Manandhar, Anju; Shekoofa, Avat; Rosas-Anderson, Pablo; Bagherzadi, Laleh; Schoppach, Remy; Sadok, Walid; Rufty, Thomas W

2017-04-01

Theoretical derivation predicted growth retardation due to pot water limitations, i.e., pot binding. Experimental observations were consistent with these limitations. Combined, these results indicate a need for caution in high-throughput screening and phenotyping. Pot experiments are a mainstay in many plant studies, including the current emphasis on developing high-throughput, phenotyping systems. Pot studies can be vulnerable to decreased physiological activity of the plants particularly when pot volume is small, i.e., "pot binding". It is necessary to understand the conditions under which pot binding may exist to avoid the confounding influence of pot binding in interpreting experimental results. In this paper, a derivation is offered that gives well-defined conditions for the occurrence of pot binding based on restricted water availability. These results showed that not only are pot volume and plant size important variables, but the potting media is critical. Artificial potting mixtures used in many studies, including many high-throughput phenotyping systems, are particularly susceptible to the confounding influences of pot binding. Experimental studies for several crop species are presented that clearly show the existence of thresholds of plant leaf area at which various pot sizes and potting media result in the induction of pot binding even though there may be no immediate, visual plant symptoms. The derivation and experimental results showed that pot binding can readily occur in plant experiments if care is not given to have sufficiently large pots, suitable potting media, and maintenance of pot water status. Clear guidelines are provided for avoiding the confounding effects of water-limited pot binding in studying plant phenotype.

Placental Abruption and Perinatal Mortality With Preterm Delivery as a Mediator: Disentangling Direct and Indirect Effects

PubMed Central

Ananth, Cande V.; VanderWeele, Tyler J.

2011-01-01

The authors use recent methodology in causal inference to disentangle the direct and indirect effects that operate through a mediator in an exposure-response association paradigm. They demonstrate how total effects can be partitioned into direct and indirect effects even when the exposure and mediator interact. The impact of bias due to unmeasured confounding on the exposure-response association is assessed through a series of sensitivity analyses. These methods are applied to a problem in perinatal epidemiology to examine the extent to which the effect of abruption on perinatal mortality is mediated through preterm delivery. Data on over 26 million US singleton births (1995–2002) were utilized. Risks of mortality among abruption and nonabruption births were 102.7 and 6.2 per 1,000 births, respectively. Risk ratios of the natural direct and indirect (preterm delivery-mediated) effects of abruption on mortality were 10.18 (95% confidence interval: 9.80, 10.58) and 1.35 (95% confidence interval: 1.33, 1.38), respectively. The proportion of increased mortality risk mediated through preterm delivery was 28.1%, with even higher proportions associated with deliveries at earlier gestational ages. Sensitivity analyses underscore that the qualitative conclusions of some mediated effects and substantial direct effects are reasonably robust to unmeasured confounding of a fairly considerable magnitude. PMID:21430195

Why Do Thin People Have Elevated All-Cause Mortality? Evidence on Confounding and Reverse Causality in the Association of Adiposity and COPD from the British Women’s Heart and Health Study

PubMed Central

Dale, Caroline; Nüesch, Eveline; Prieto-Merino, David; Choi, Minkyoung; Amuzu, Antoinette; Ebrahim, Shah; Casas, Juan P.; Davey-Smith, George

2015-01-01

Low adiposity has been linked to elevated mortality from several causes including respiratory disease. However, this could arise from confounding or reverse causality. We explore the association between two measures of adiposity (BMI and WHR) with COPD in the British Women’s Heart and Health Study including a detailed assessment of the potential for confounding and reverse causality for each adiposity measure. Low BMI was found to be associated with increased COPD risk while low WHR was not (OR = 2.2; 95% CI 1.3 – 3.1 versus OR = 1.2; 95% CI 0.7 – 1.6). Potential confounding variables (e.g. smoking) and markers of ill-health (e.g. unintentional weight loss) were found to be higher in low BMI but not in low WHR. Women with low BMI have a detrimental profile across a broad range of health markers compared to women with low WHR, and women with low WHR do not appear to have an elevated COPD risk, lending support to the hypothesis that WHR is a less confounded measure of adiposity than BMI. Low adiposity does not in itself appear to increase the risk of respiratory disease, and the apparent adverse consequences of low BMI may be due to reverse causation and confounding. PMID:25884834

Stability and change in health behaviours as predictors for disability pension: a prospective cohort study of Swedish twins

PubMed Central

2011-01-01

Background Stability or changes of health behaviours have not been studied in association with incidence of disability pension (DP). The aims were to (1) investigate if stability or changes in health behaviours predict DP due to musculoskeletal diagnosis (MSD), (2) to evaluate if an association exists for DP in general, and (3) after taking familial confounding into account. Methods The study sample was 16,713 like-sexed twin individuals born in Sweden between 1935-1958 (6195 complete twin pairs) who had participated in two surveys 25 years apart, were alive, and not pensioned at the time of the latest survey. Cox proportional hazards analysis was used to assess the associations (hazard ratios (HR) with 95% confidence intervals (CI)) between stability and change in health behaviours (physical activity, tobacco and alcohol use, body mass index (BMI)), and number of pain locations collected at two time points 25 years apart and the incidence of DP until 2008. Results During the follow-up, 1843 (11%) individuals were granted DP with 747 of these due to MSD. A higher proportion of women were granted DP than men. Increase in BMI and stable use of tobacco products were predictors for DP due to MSD (HR 1.21-1.48) and DP in general (HR 1.10-1.41). The stability in the frequency of physical activity and increased frequency of physical activity were protective factors for DP due to MSD only when accounting for familial confounding. However, the number of pain locations (stability, increase, or decrease) was the strongest predictor for future DP due to MSD (HR 3.69, CI 2.99-4.56) and DP in general (HR 2.15, CI 1.92-2.42). In discordant pair analysis, the HRs for pain were lower, indicating potential familial confounding. Conclusions Health behaviours in adulthood, including an increase in pain locations were associated with the incidence of DP. The association between physical activity and DP was especially related to adulthood choices or habits, i.e., the individual decision about frequency of exercising. Thus, it is important to e.g. increase public awareness of the potential beneficial effects of exercise throughout life to avoid permanent exclusion from the labour market for medical reasons. PMID:21880151

Stability and change in health behaviours as predictors for disability pension: a prospective cohort study of Swedish twins.

PubMed

Ropponen, Annina; Narusyte, Jurgita; Alexanderson, Kristina; Svedberg, Pia

2011-08-31

Stability or changes of health behaviours have not been studied in association with incidence of disability pension (DP). The aims were to (1) investigate if stability or changes in health behaviours predict DP due to musculoskeletal diagnosis (MSD), (2) to evaluate if an association exists for DP in general, and (3) after taking familial confounding into account. The study sample was 16,713 like-sexed twin individuals born in Sweden between 1935-1958 (6195 complete twin pairs) who had participated in two surveys 25 years apart, were alive, and not pensioned at the time of the latest survey. Cox proportional hazards analysis was used to assess the associations (hazard ratios (HR) with 95% confidence intervals (CI)) between stability and change in health behaviours (physical activity, tobacco and alcohol use, body mass index (BMI)), and number of pain locations collected at two time points 25 years apart and the incidence of DP until 2008. During the follow-up, 1843 (11%) individuals were granted DP with 747 of these due to MSD. A higher proportion of women were granted DP than men. Increase in BMI and stable use of tobacco products were predictors for DP due to MSD (HR 1.21-1.48) and DP in general (HR 1.10-1.41). The stability in the frequency of physical activity and increased frequency of physical activity were protective factors for DP due to MSD only when accounting for familial confounding. However, the number of pain locations (stability, increase, or decrease) was the strongest predictor for future DP due to MSD (HR 3.69, CI 2.99-4.56) and DP in general (HR 2.15, CI 1.92-2.42). In discordant pair analysis, the HRs for pain were lower, indicating potential familial confounding. Health behaviours in adulthood, including an increase in pain locations were associated with the incidence of DP. The association between physical activity and DP was especially related to adulthood choices or habits, i.e., the individual decision about frequency of exercising. Thus, it is important to e.g. increase public awareness of the potential beneficial effects of exercise throughout life to avoid permanent exclusion from the labour market for medical reasons.

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.

A prospective cohort study of disability pension due to mental diagnoses: the importance of health factors and behaviors

PubMed Central

2013-01-01

Background Previous studies have found associations between various health factors and behaviors and mental disorders. However, knowledge of such associations with disability pension (DP) due to mental diagnoses is scarce. Moreover, the influence of familial factors (genetics and family background) on the associations are mainly unknown. The aim of the study was to investigate associations between health factors and behaviors and future DP due to mental diagnoses in a twin cohort, accounting for familial confounding. Methods A prospective cohort study of Swedish twins (N=28 613), including survey data and national register data on DP and other background factors was conducted. Cox proportional hazards regression models were used to calculate hazard ratios (HR) with 95% confidence intervals (CI) for the whole twin cohort, and for discordant twin pairs. Results During follow-up 1998–2008 (median 10 years), 2.2% of the cohort was granted a DP with a mental diagnosis. In the fully adjusted analyses of the whole cohort, the associations of poor or moderate self-rated health (SRH), under- or overweight, former or current tobacco use, or being an abstainer from alcohol were significantly associated with risk of DP due to mental diagnoses. Analyses of discordant twin pairs confirmed all these associations, except for current tobacco use, being independent from familial confounding. Exclusion of individuals with current or previous depression or anxiety at baseline did not influence the associations found. Conclusions Poor or moderate SRH, under- or overweight, former tobacco use or being an abstainer from alcohol seem to be strong direct predictors of DP due to mental diagnoses, independently of several confounders of this study, including familial factors. PMID:23816331

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

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.

Gateway Effects: Why the Cited Evidence Does Not Support Their Existence for Low-Risk Tobacco Products (and What Evidence Would)

PubMed Central

Phillips, Carl V.

2015-01-01

It is often claimed that low-risk drugs still create harm because of “gateway effects”, in which they cause the use of a high-risk alternative. Such claims are popular among opponents of tobacco harm reduction, claiming that low-risk tobacco products (e.g., e-cigarettes, smokeless tobacco) cause people to start smoking, sometimes backed by empirical studies that ostensibly support the claim. However, these studies consistently ignore the obvious alternative causal pathways, particularly that observed associations might represent causation in the opposite direction (smoking causes people to seek low-risk alternatives) or confounding (the same individual characteristics increase the chance of using any tobacco product). Due to these complications, any useful analysis must deal with simultaneity and confounding by common cause. In practice, existing analyses seem almost as if they were designed to provide teaching examples about drawing simplistic and unsupported causal conclusions from observed associations. The present analysis examines what evidence and research strategies would be needed to empirically detect such a gateway effect, if there were one, explaining key methodological concepts including causation and confounding, examining the logic of the claim, identifying potentially useful data, and debunking common fallacies on both sides of the argument, as well as presenting an extended example of proper empirical testing. The analysis demonstrates that none of the empirical studies to date that are purported to show a gateway effect from tobacco harm reduction products actually does so. The observations and approaches can be generalized to other cases where observed association of individual characteristics in cross-sectional data could result from any of several causal relationships. PMID:26006122

Prenatal Stress due to a Natural Disaster Predicts Adiposity in Childhood: The Iowa Flood Study

PubMed Central

Dancause, Kelsey N.; Laplante, David P.; Hart, Kimberly J.; O'Hara, Michael W.; Brunet, Alain

2015-01-01

Prenatal stress can affect lifelong physical growth, including increased obesity risk. However, human studies remain limited. Natural disasters provide models of independent stressors unrelated to confounding maternal characteristics. We assessed degree of objective hardship and subjective distress in women pregnant during severe flooding. At ages 2.5 and 4 years we assessed body mass index (BMI), subscapular plus triceps skinfolds (SS + TR, an index of total adiposity), and SS : TR ratio (an index of central adiposity) in their children (n = 106). Hierarchical regressions controlled first for several potential confounds. Controlling for these, flood exposure during early gestation predicted greater BMI increase from age 2.5 to 4, as well as total adiposity at 2.5. Greater maternal hardship and distress due to the floods, as well as other nonflood life events during pregnancy, independently predicted greater increase in total adiposity between 2.5 and 4 years. These results support the hypothesis that prenatal stress increases adiposity beginning in childhood and suggest that early gestation is a sensitive period. Results further highlight the additive effects of maternal objective and subjective stress, life events, and depression, emphasizing the importance of continued studies on multiple, detailed measures of maternal mental health and experience in pregnancy and child growth. PMID:25874124

Prenatal stress due to a natural disaster predicts adiposity in childhood: the Iowa Flood Study.

PubMed

Dancause, Kelsey N; Laplante, David P; Hart, Kimberly J; O'Hara, Michael W; Elgbeili, Guillaume; Brunet, Alain; King, Suzanne

2015-01-01

Prenatal stress can affect lifelong physical growth, including increased obesity risk. However, human studies remain limited. Natural disasters provide models of independent stressors unrelated to confounding maternal characteristics. We assessed degree of objective hardship and subjective distress in women pregnant during severe flooding. At ages 2.5 and 4 years we assessed body mass index (BMI), subscapular plus triceps skinfolds (SS + TR, an index of total adiposity), and SS : TR ratio (an index of central adiposity) in their children (n = 106). Hierarchical regressions controlled first for several potential confounds. Controlling for these, flood exposure during early gestation predicted greater BMI increase from age 2.5 to 4, as well as total adiposity at 2.5. Greater maternal hardship and distress due to the floods, as well as other nonflood life events during pregnancy, independently predicted greater increase in total adiposity between 2.5 and 4 years. These results support the hypothesis that prenatal stress increases adiposity beginning in childhood and suggest that early gestation is a sensitive period. Results further highlight the additive effects of maternal objective and subjective stress, life events, and depression, emphasizing the importance of continued studies on multiple, detailed measures of maternal mental health and experience in pregnancy and child growth.

The Asymmetrical Effects of Divided Attention on Encoding and Retrieval Processes: A Different View Based on an Interference with the Episodic Register

PubMed Central

Guez, Jonathan; Naveh-Benjamin, Moshe

2013-01-01

In this study, we evaluate the conceptualization of encoding and retrieval processes established in previous studies that used a divided attention (DA) paradigm. These studies indicated that there were considerable detrimental effects of DA at encoding on later memory performance, but only minimal effects, if any, on divided attention at retrieval. We suggest that this asymmetry in the effects of DA on memory can be due, at least partially, to a confound between the memory phase (encoding and retrieval) and the memory requirements of the task (memory “for” encoded information versus memory “at” test). To control for this confound, we tested memory for encoded information and for retrieved information by introducing a second test that assessed memory for the retrieved information from the first test. We report the results of four experiments that use measures of memory performance, retrieval latency, and performance on the concurrent task, all of which consistently show that DA at retrieval strongly disrupts later memory for the retrieved episode, similarly to the effects of DA at encoding. We suggest that these symmetrical disruptive effects of DA at encoding and retrieval on later retrieval reflect a disruption of an episodic buffer (EB) or episodic register component (ER), rather than a failure of encoding or retrieval operations per se. PMID:24040249

The asymmetrical effects of divided attention on encoding and retrieval processes: a different view based on an interference with the episodic register.

PubMed

Guez, Jonathan; Naveh-Benjamin, Moshe

2013-01-01

In this study, we evaluate the conceptualization of encoding and retrieval processes established in previous studies that used a divided attention (DA) paradigm. These studies indicated that there were considerable detrimental effects of DA at encoding on later memory performance, but only minimal effects, if any, on divided attention at retrieval. We suggest that this asymmetry in the effects of DA on memory can be due, at least partially, to a confound between the memory phase (encoding and retrieval) and the memory requirements of the task (memory "for" encoded information versus memory "at" test). To control for this confound, we tested memory for encoded information and for retrieved information by introducing a second test that assessed memory for the retrieved information from the first test. We report the results of four experiments that use measures of memory performance, retrieval latency, and performance on the concurrent task, all of which consistently show that DA at retrieval strongly disrupts later memory for the retrieved episode, similarly to the effects of DA at encoding. We suggest that these symmetrical disruptive effects of DA at encoding and retrieval on later retrieval reflect a disruption of an episodic buffer (EB) or episodic register component (ER), rather than a failure of encoding or retrieval operations per se.

Educational gains in cause-specific mortality: Accounting for cognitive ability and family-level confounders using propensity score weighting.

PubMed

Bijwaard, Govert E; Myrskylä, Mikko; Tynelius, Per; Rasmussen, Finn

2017-07-01

A negative educational gradient has been found for many causes of death. This association may be partly explained by confounding factors that affect both educational attainment and mortality. We correct the cause-specific educational gradient for observed individual background and unobserved family factors using an innovative method based on months lost due to a specific cause of death re-weighted by the probability of attaining a higher educational level. We use data on men with brothers from the Swedish Military Conscription Registry (1951-1983), linked to administrative registers. This dataset of some 700,000 men allows us to distinguish between five education levels and many causes of death. The empirical results reveal that raising the educational level from primary to tertiary would result in an additional 20 months of survival between ages 18 and 63. This improvement in mortality is mainly attributable to fewer deaths from external causes. The highly educated gain more than nine months due to the reduction in deaths from external causes, but gain only two months due to the reduction in cancer mortality and four months due to the reduction in cardiovascular mortality. Ignoring confounding would lead to an underestimation of the gains by educational attainment, especially for the less educated. Our results imply that if the education distribution of 50,000 Swedish men from the 1951 cohort were replaced with that of the corresponding 1983 cohort, 22% of the person-years that were lost to death between ages 18 and 63 would have been saved for this cohort. Copyright © 2017 Elsevier Ltd. All rights reserved.

Propensity score matching with clustered data. An application to the estimation of the impact of caesarean section on the Apgar score.

PubMed

Arpino, Bruno; Cannas, Massimo

2016-05-30

This article focuses on the implementation of propensity score matching for clustered data. Different approaches to reduce bias due to cluster-level confounders are considered and compared using Monte Carlo simulations. We investigated methods that exploit the clustered structure of the data in two ways: in the estimation of the propensity score model (through the inclusion of fixed or random effects) or in the implementation of the matching algorithm. In addition to a pure within-cluster matching, we also assessed the performance of a new approach, 'preferential' within-cluster matching. This approach first searches for control units to be matched to treated units within the same cluster. If matching is not possible within-cluster, then the algorithm searches in other clusters. All considered approaches successfully reduced the bias due to the omission of a cluster-level confounder. The preferential within-cluster matching approach, combining the advantages of within-cluster and between-cluster matching, showed a relatively good performance both in the presence of big and small clusters, and it was often the best method. An important advantage of this approach is that it reduces the number of unmatched units as compared with a pure within-cluster matching. We applied these methods to the estimation of the effect of caesarean section on the Apgar score using birth register data. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Adjusting for reverse causation to estimate the effect of obesity on mortality after incident heart failure in the Atherosclerosis Risk in Communities (ARIC) study.

PubMed

Shakiba, Maryam; Soori, Hamid; Mansournia, Mohammad Ali; Nazari, Seyed Saeed Hashemi; Salimi, Yahya

2016-01-01

The lower mortality rate of obese patients with heart failure (HF) has been partly attributed to reverse causation bias due to weight loss caused by disease. Using data about weight both before and after HF, this study aimed to adjust for reverse causation and examine the association of obesity both before and after HF with mortality. Using the Atherosclerosis Risk in Communities (ARIC) study, 308 patients with data available from before and after the incidence of HF were included. Pre-morbid and post-morbid obesity were defined based on body mass index measurements at least three months before and after incident HF. The associations of pre-morbid and post-morbid obesity and weight change with survival after HF were evaluated using a Cox proportional hazard model. Pre-morbid obesity was associated with higher mortality (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.04 to 2.49) but post-morbid obesity was associated with increased survival (HR, 0.57; 95% CI, 0.37 to 0.88). Adjusting for weight change due to disease as a confounder of the obesity-mortality relationship resulted in the absence of any significant associations between post-morbid obesity and mortality. This study demonstrated that controlling for reverse causality by adjusting for the confounder of weight change may remove or reverse the protective effect of obesity on mortality among patients with incident HF.

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.

Inflammasomes make the case for littermate-controlled experimental design in studying host-microbiota interactions.

PubMed

Mamantopoulos, Michail; Ronchi, Francesca; McCoy, Kathy D; Wullaert, Andy

2018-04-19

Several human diseases are thought to evolve due to a combination of host genetic mutations and environmental factors that include alterations in intestinal microbiota composition termed dysbiosis. Although in some cases, host genetics may shape the gut microbiota and enable it to provoke disease, experimentally disentangling cause and consequence in such host-microbe interactions requires strict control over non-genetic confounding factors. Mouse genetic studies previously proposed Nlrp6/ASC inflammasomes as innate immunity regulators of the intestinal ecosystem. In contrast, using littermate-controlled experimental setups, we recently showed that Nlrp6/ASC inflammasomes do not alter the gut microbiota composition. Our analyses indicated that maternal inheritance and long-term separate housing are non-genetic confounders that preclude the use of non-littermate mice when analyzing host genetic effects on intestinal ecology. Here, we summarize and discuss our gut microbiota analyses in inflammasome-deficient mice for illustrating the importance of littermate experimental design in studying host-microbiota interactions.

The role of sex and body weight on the metabolic effects of high-fat diet in C57BL/6N mice

PubMed Central

Ingvorsen, C; Karp, N A; Lelliott, C J

2017-01-01

Background: 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. Methods: 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. Results: 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. Conclusion: 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. PMID:28394359

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.

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.

Factors influencing tests of auditory processing: a perspective on current issues and relevant concerns.

PubMed

Cacace, Anthony T; McFarland, Dennis J

2013-01-01

Tests of auditory perception, such as those used in the assessment of central auditory processing disorders ([C]APDs), represent a domain in audiological assessment where measurement of this theoretical construct is often confounded by nonauditory abilities due to methodological shortcomings. These confounds include the effects of cognitive variables such as memory and attention and suboptimal testing paradigms, including the use of verbal reproduction as a form of response selection. We argue that these factors need to be controlled more carefully and/or modified so that their impact on tests of auditory and visual perception is only minimal. To advocate for a stronger theoretical framework than currently exists and to suggest better methodological strategies to improve assessment of auditory processing disorders (APDs). Emphasis is placed on adaptive forced-choice psychophysical methods and the use of matched tasks in multiple sensory modalities to achieve these goals. Together, this approach has potential to improve the construct validity of the diagnosis, enhance and develop theory, and evolve into a preferred method of testing. Examination of methods commonly used in studies of APDs. Where possible, currently used methodology is compared to contemporary psychophysical methods that emphasize computer-controlled forced-choice paradigms. In many cases, the procedures used in studies of APD introduce confounding factors that could be minimized if computer-controlled forced-choice psychophysical methods were utilized. Ambiguities of interpretation, indeterminate diagnoses, and unwanted confounds can be avoided by minimizing memory and attentional demands on the input end and precluding the use of response-selection strategies that use complex motor processes on the output end. Advocated are the use of computer-controlled forced-choice psychophysical paradigms in combination with matched tasks in multiple sensory modalities to enhance the prospect of obtaining a valid diagnosis. American Academy of Audiology.

A Bayesian Framework to Account for Complex Non-Genetic Factors in Gene Expression Levels Greatly Increases Power in eQTL Studies

PubMed Central

Durbin, Richard; Winn, John

2010-01-01

Gene expression measurements are influenced by a wide range of factors, such as the state of the cell, experimental conditions and variants in the sequence of regulatory regions. To understand the effect of a variable of interest, such as the genotype of a locus, it is important to account for variation that is due to confounding causes. Here, we present VBQTL, a probabilistic approach for mapping expression quantitative trait loci (eQTLs) that jointly models contributions from genotype as well as known and hidden confounding factors. VBQTL is implemented within an efficient and flexible inference framework, making it fast and tractable on large-scale problems. We compare the performance of VBQTL with alternative methods for dealing with confounding variability on eQTL mapping datasets from simulations, yeast, mouse, and human. Employing Bayesian complexity control and joint modelling is shown to result in more precise estimates of the contribution of different confounding factors resulting in additional associations to measured transcript levels compared to alternative approaches. We present a threefold larger collection of cis eQTLs than previously found in a whole-genome eQTL scan of an outbred human population. Altogether, 27% of the tested probes show a significant genetic association in cis, and we validate that the additional eQTLs are likely to be real by replicating them in different sets of individuals. Our method is the next step in the analysis of high-dimensional phenotype data, and its application has revealed insights into genetic regulation of gene expression by demonstrating more abundant cis-acting eQTLs in human than previously shown. Our software is freely available online at http://www.sanger.ac.uk/resources/software/peer/. PMID:20463871

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.

Survival analysis using inverse probability of treatment weighted methods based on the generalized propensity score.

PubMed

Sugihara, Masahiro

2010-01-01

In survival analysis, treatment effects are commonly evaluated based on survival curves and hazard ratios as causal treatment effects. In observational studies, these estimates may be biased due to confounding factors. The inverse probability of treatment weighted (IPTW) method based on the propensity score is one of the approaches utilized to adjust for confounding factors between binary treatment groups. As a generalization of this methodology, we developed an exact formula for an IPTW log-rank test based on the generalized propensity score for survival data. This makes it possible to compare the group differences of IPTW Kaplan-Meier estimators of survival curves using an IPTW log-rank test for multi-valued treatments. As causal treatment effects, the hazard ratio can be estimated using the IPTW approach. If the treatments correspond to ordered levels of a treatment, the proposed method can be easily extended to the analysis of treatment effect patterns with contrast statistics. In this paper, the proposed method is illustrated with data from the Kyushu Lipid Intervention Study (KLIS), which investigated the primary preventive effects of pravastatin on coronary heart disease (CHD). The results of the proposed method suggested that pravastatin treatment reduces the risk of CHD and that compliance to pravastatin treatment is important for the prevention of CHD. (c) 2009 John Wiley & Sons, Ltd.

Interpreting large-scale experiments on effects of trawling on benthic fauna: an empirical test of the potential effects of spatial confounding in experiments without replicated control and trawled areas.

PubMed

Lindegarth; Valentinsson; Hansson; Ulmestrand

2000-03-15

Disturbances due to trawling and dredging is a serious threat to assemblages of benthic marine animals. We tested hypotheses about effects of trawling on benthic assemblages in a manipulative field experiment, using gear and intensities relevant to future management of trawling in a Swedish fjord. Three trawled and three control sites were sampled at several times before and after trawling was initiated. This paper describes how conclusions about effects of trawling might differ between experiments involving replicate sites and experiments using only one trawled and one control site, as in several recent studies. Analyses of selected taxa showed that abundances of many species changed differently among control sites. Differences in temporal change between pairs of single trawled and control sites were also frequent. Neither the quantitative nor the qualitative nature of differences between treatments could, however, be coherently interpreted among the different combinations of trawled and control sites. This is consistent with results obtained from analyses using all sites, which showed no consistent effects of trawling on any of these taxa. These results provide empirical evidence that spatial confounding may cause serious problems to formal interpretation of experiments, which use only one control and one trawled area. Such potential problems can best be solved by ensuring that the study incorporates more than one control site.

Dissociating the influence of familiarity and meaningfulness from word frequency in naming and lexical decision performance.

PubMed

Colombo, Lucia; Pasini, Margherita; Balota, David A

2006-09-01

Performance in two experiments was compared on a list of words of high and low frequency in which familiarity/meaningfulness (FM) was balanced and on a list of high- and low-frequency words in which FM was confounded with frequency (i.e., high frequency--high familiarity vs. low frequency--low familiarity). Both repetition and task (lexical decision and naming) were investigated. In the lexical decision task of Experiment 1, both frequency and repetition effects were larger in the list with FM confounded than in the list with FM matched. In the naming task, frequency and repetition effects and their interaction were significant, but there was no influence of FM list context. In Experiment 2, in which the repetitions occurred across blocks, as opposed to randomly intermixed within a list, similar results were found; however, there was no interaction between list and repetition. The results suggest that an evaluation of items in terms of their meaning and familiarity explains a large part of the variance, only in lexical decision. These dimensions may be cued both by subjective feelings of familiarity and the extent to which semantic information is available and by episodic traces due to recent encounters with the item.

Effects of low-dose radiation - a correlation study.

PubMed

Edling, C; Comba, P; Axelson, O; Flodin, U

1982-01-01

The effects of low-dose radiation have been a matter of controversy over the years, and the epidemiologic results have been conflicting. A couple of recent studies have indicated a possible impact on lung cancer mortality from exposure to indoor levels of radon and radon daughters. In this study, selected mortality rates, ie, lung cancer, pancreatic cancer, breast cancer (females only), leukemia, and multiple myeloma were correlated for the counties of Sweden with estimates of average background radiation exposure in these areas. Significant correlations were obtained for lung cancer (males, r = 0.46; females r = 0.55) and pancreatic cancer (males, r = 0.59; females, r = 0.40) , and there was a borderline correlation (r = 0.36; p = 0.04) for leukemia in males. In all, there were positive correlations for eight out of the nine computations made. Since background radiation correlates with urbanization and therefore with smoking, air pollution, etc, the correlations might be spurious due to confounding; on the other hand confounding is a reciprocal phenomenon which suggests that background radiation should to be taken into consideration when widespread risk factors like smoking, coffee drinking, general air pollution, etc, are studied.

Youth appraisals of inter-parental conflict and genetic and environmental contributions to attention-deficit hyperactivity disorder: examination of GxE effects in a twin sample.

PubMed

Nikolas, Molly; Klump, Kelly L; Burt, S Alexandra

2012-05-01

Identification of gene x environment interactions (GxE) for attention-deficit hyperactivity disorder (ADHD) is a crucial component to understanding the mechanisms underpinning the disorder, as prior work indicates large genetic influences and numerous environmental risk factors. Building on prior research, children's appraisals of self-blame were examined as a psychosocial moderator of latent etiological influences on ADHD via biometric twin models, which provide an omnibus test of GxE while managing the potential confound of gene-environment correlation. Participants were 246 twin pairs (total n = 492) ages 6-16 years. ADHD behaviors were assessed via mother report on the Child Behavior Checklist. To assess level of self-blame, each twin completed the Children's Perception of Inter-parental Conflict scale. Two biometric GxE models were fit to the data. The first model revealed a significant decrease in genetic effects and a significant increase in unique environmental influences on ADHD with increasing levels of self-blame. These results generally persisted even after controlling for confounding effects due to gene-environment correlation in the second model. Results suggest that appraisals of self-blame in relation to inter-parental conflict may act as a key moderator of etiological contributions to ADHD.

Pre-conception and prenatal alcohol exposure from mothers and fathers drinking and head circumference: results from the Norwegian Mother-Child Study (MoBa).

PubMed

Zuccolo, Luisa; DeRoo, Lisa A; Wills, Andrew K; Davey Smith, George; Suren, Pål; Roth, Christine; Stoltenberg, Camilla; Magnus, Per

2016-12-23

Although microcephaly is a feature of Fetal Alcohol Syndrome, it is currently unknown whether low-to-moderate prenatal alcohol exposure affects head circumference. Small magnitude associations reported in observational studies are likely to be misleading due to confounding and misclassification biases. Alternative analytical approaches such as the use of family negative controls (e.g. comparing the effects of maternal and paternal exposure) could help disentangle causal effects. We investigated the association of maternal and paternal alcohol drinking before and early in pregnancy with infant head circumference, using data from 68,244 mother-father-offspring trios from the Norwegian Mother and Child Cohort Study (MoBa) (1999-2009). In analyses adjusted for potential confounders, we found no consistent pattern of association between maternal or paternal alcohol intake before or during pregnancy and offspring head circumference modelled as a continuous outcome. However, we found higher odds of microcephaly at birth for higher paternal, but not maternal, alcohol consumption before pregnancy, and similar but weaker effect estimates for first trimester drinking. Associations with paternal drinking before pregnancy were unexpected and should be regarded as hypothesis generating, until independently replicated, although potentially important given the absence of guidelines on safe drinking levels for men in couples trying for a pregnancy.

Youth Appraisals of Inter-parental Conflict and Genetic and Environmental Contributions to Attention-Deficit Hyperactivity Disorder: Examination of G×E Effects in a Twin Sample

PubMed Central

Klump, Kelly L.; Burt, S. Alexandra

2012-01-01

Identification of gene × environment interactions (GxE) for attention-deficit hyperactivity disorder (ADHD) is a crucial component to understanding the mechanisms underpinning the disorder, as prior work indicates large genetic influences and numerous environmental risk factors. Building on prior research, children's appraisals of self-blame were examined as a psychosocial moderator of latent etiological influences on ADHD via biometric twin models, which provide an omnibus test of GxE while managing the potential confound of gene-environment correlation. Participants were 246 twin pairs (total n=492) ages 6–16 years. ADHD behaviors were assessed via mother report on the Child Behavior Checklist. To assess level of self-blame, each twin completed the Children's Perception of Inter-parental Conflict scale. Two biometric GxE models were fit to the data. The first model revealed a significant decrease in genetic effects and a significant increase in unique environmental influences on ADHD with increasing levels of self-blame. These results generally persisted even after controlling for confounding effects due to gene-environment correlation in the second model. Results suggest that appraisals of self-blame in relation to inter-parental conflict may act as a key moderator of etiological contributions to ADHD. PMID:22006350

Anemia of inflammation is related to cognitive impairment among children in Leyte, the Philippines.

PubMed

Olson, Courtney L; Acosta, Luz P; Hochberg, Natasha S; Olveda, Remigio M; Jiz, Mario; McGarvey, Stephen T; Kurtis, Jonathan D; Bellinger, David C; Friedman, Jennifer F

2009-10-20

Many studies have addressed the relationship between iron deficiency anemia (IDA) and cognitive impairment, but none have evaluated the role of non-iron deficiency anemia (NIDA). One of the main causes of NIDA in developing countries is AI, largely due to infectious diseases, whereby iron is shunted away from bio-available forms to storage forms, making it less accessible for use by host tissues. The objective of this study was to determine the effect of NIDA, due largely to AI in this context, on cognitive function after adjustment for potential confounders. This cross-sectional study was conducted in Leyte, The Philippines among 322 children ages 7-18 years. Blood samples were collected and analyzed at the time of cognition testing. Three stool samples were collected and evaluated by the Kato Katz method for quantitative assessment for Schistosoma japonicum and geo-helminth infection. Socio-economic status (SES) was evaluated by survey. Linear regression models were used to quantify the adjusted relationship between performance in different cognitive domains and both IDA and NIDA. After adjusting for age, sex, SES and nutritional status, children in the NIDA had lower scores on the PNIT (P = <0.05) and the WRAML memory domain (P<0.05) compared to children in the non-anemic group. Children in the IDA had lower performance on the PNIT compared to the non-anemic group after controlling for potential confounders (P<0.05). NIDA, predominantly due to AI in this context, was related to lower performance on two tests of cognitive function. This is likely due to decreased delivery of iron to host tissues in this context, including the CNS.

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

Revisiting the Table 2 fallacy: A motivating example examining preeclampsia and preterm birth.

PubMed

Bandoli, Gretchen; Palmsten, Kristin; Chambers, Christina D; Jelliffe-Pawlowski, Laura L; Baer, Rebecca J; Thompson, Caroline A

2018-05-21

A "Table Fallacy," as coined by Westreich and Greenland, reports multiple adjusted effect estimates from a single model. This practice, which remains common in published literature, can be problematic when different types of effect estimates are presented together in a single table. The purpose of this paper is to quantitatively illustrate this potential for misinterpretation with an example estimating the effects of preeclampsia on preterm birth. We analysed a retrospective population-based cohort of 2 963 888 singleton births in California between 2007 and 2012. We performed a modified Poisson regression to calculate the total effect of preeclampsia on the risk of PTB, adjusting for previous preterm birth. pregnancy alcohol abuse, maternal education, and maternal socio-demographic factors (Model 1). In subsequent models, we report the total effects of previous preterm birth, alcohol abuse, and education on the risk of PTB, comparing and contrasting the controlled direct effects, total effects, and confounded effect estimates, resulting from Model 1. The effect estimate for previous preterm birth (a controlled direct effect in Model 1) increased 10% when estimated as a total effect. The risk ratio for alcohol abuse, biased due to an uncontrolled confounder in Model 1, was reduced by 23% when adjusted for drug abuse. The risk ratio for maternal education, solely a predictor of the outcome, was essentially unchanged. Reporting multiple effect estimates from a single model may lead to misinterpretation and lack of reproducibility. This example highlights the need for careful consideration of the types of effects estimated in statistical models. © 2018 John Wiley & Sons Ltd.

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…

Volunteering and mortality risk: a partner-controlled quasi-experimental design.

PubMed

O'Reilly, Dermot; Rosato, Michael; Moriarty, John; Leavey, Gerard

2017-08-01

The consensus that volunteering is associated with a lower mortality risk is derived from a body of observational studies and therefore vulnerable to uncontrolled or residual confounding. This potential limitation is likely to be particularly problematic for volunteers who, by definition, are self-selected and known to be significantly different from non-volunteers across a range of factors associated with better survival. This is a census-based record-linkage study of 308 733 married couples aged 25 and over, including 100 571 volunteers, with mortality follow-up for 33 months. We used a standard Cox model to examine whether mortality risk in the partners of volunteers was influenced by partner volunteering status-something expected if the effects of volunteering on mortality risk were due to shared household or behavioural characteristics. Volunteers were general more affluent, better educated and more religious than their non-volunteering peers; they also had a lower mortality risk [hazard ratio (HR)adj = 0.78: 95% confidence interval (CI) = 0.71, 0.85 for males and HRadj = 0.77: 95% CI = 0.68, 0.88 for females]. However, amongst cohort members who were not volunteers, having a partner who was a volunteer was not associated with a mortality advantage (HRadj = 1.01: 95% CI = 0.92, 1.11 for men and HRadj = 1.00: 95% CI = 0.88, 1.13 women). This study provides further evidence that the lower mortality associated with volunteering is unlikely to be due to health selection or to residual confounding arising from unmeasured selection effects within households. It therefore increases the plausibility of a direct causal effect. © The Author 2017; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association

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.

Neuroticism explains unwanted variance in Implicit Association Tests of personality: possible evidence for an affective valence confound.

PubMed

Fleischhauer, Monika; Enge, Sören; Miller, Robert; Strobel, Alexander; Strobel, Anja

2013-01-01

Meta-analytic data highlight the value of the Implicit Association Test (IAT) as an indirect measure of personality. Based on evidence suggesting that confounding factors such as cognitive abilities contribute to the IAT effect, this study provides a first investigation of whether basic personality traits explain unwanted variance in the IAT. In a gender-balanced sample of 204 volunteers, the Big-Five dimensions were assessed via self-report, peer-report, and IAT. By means of structural equation modeling (SEM), latent Big-Five personality factors (based on self- and peer-report) were estimated and their predictive value for unwanted variance in the IAT was examined. In a first analysis, unwanted variance was defined in the sense of method-specific variance which may result from differences in task demands between the two IAT block conditions and which can be mirrored by the absolute size of the IAT effects. In a second analysis, unwanted variance was examined in a broader sense defined as those systematic variance components in the raw IAT scores that are not explained by the latent implicit personality factors. In contrast to the absolute IAT scores, this also considers biases associated with the direction of IAT effects (i.e., whether they are positive or negative in sign), biases that might result, for example, from the IAT's stimulus or category features. None of the explicit Big-Five factors was predictive for method-specific variance in the IATs (first analysis). However, when considering unwanted variance that goes beyond pure method-specific variance (second analysis), a substantial effect of neuroticism occurred that may have been driven by the affective valence of IAT attribute categories and the facilitated processing of negative stimuli, typically associated with neuroticism. The findings thus point to the necessity of using attribute category labels and stimuli of similar affective valence in personality IATs to avoid confounding due to recoding.

Inventory of forest and rangeland and detection of forest stress. [Black Hills, Manitou, Colorado, and Atlanta, Georgia test sites

NASA Technical Reports Server (NTRS)

Heller, R. C.; Aldrich, R. C.; Driscoll, R. S.; Weber, F. P. (Principal Investigator)

1974-01-01

The author has identified the following significant results. Controlled visual interpretation of one ERTS-1 scene taken at the peak of the growing season has indicated that classification to the ECOCLASS Series level is not entirely satisfactory. For five forest classes, aspen, Douglas-fir, lodgepole pine, ponderosa pine, and Spruce/fir, correct identification ranged from 60 to 70 percent. With the exception of shortgrass and wet shrubby meadow classes in the nonforest categories (81 and 100 percent correct, respectively), correct identification of the nonforest classes is so far unacceptable. The low accuracies are believed due to: (1) edge effects due to ecotones between plant community classes with apparent similar image characteristics; (2) confounding effects of amount of plant crown cover and ground surface material in the scene; and (3) variable land slope degree and aspect as it affects the image signature.

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.

Vehicle year and the risk of car crash injury

PubMed Central

Blows, S; Ivers, R; Woodward, M; Connor, J; Ameratunga, S; Norton, R

2003-01-01

Objective: To quantify the association between vehicle age and risk of car crash injury. Design and setting: Data from a population based case-control study conducted in the Auckland region in 1998/99 was used to examine the adjusted risk of car crash injury or death due to vehicle age, after controlling for a range of known confounders. Cases were all cars involved in crashes in which at least one occupant was hospitalized or killed anywhere in the Auckland region, and controls were randomly selected cars on Auckland roads. The drivers of the 571 case vehicles and 588 control vehicles completed a structured interview. Main outcome measure: Hospitalisation or death of a vehicle occupant due to car crash injury. Results: Vehicles constructed before 1984 had significantly greater chance of being involved in an injury crash than those constructed after 1994 (odds ratio 2.88, 95% confidence interval (CI) 1.20 to 6.91), after adjustment for potential confounders. There was also a trend for increasing crash risk with each one year increase in vehicle age after adjustment for potential confounders (odds ratio 1.05, 95% CI 0.99 to 1.11; p = 0.09). Conclusion: This study quantifies the increased risk of car crash injury associated with older vehicle year and confirms this as an important public health issue. PMID:14693899

Vehicle year and the risk of car crash injury.

PubMed

Blows, S; Ivers, R Q; Woodward, M; Connor, J; Ameratunga, S; Norton, R

2003-12-01

To quantify the association between vehicle age and risk of car crash injury. Data from a population based case-control study conducted in the Auckland region in 1998/99 was used to examine the adjusted risk of car crash injury or death due to vehicle age, after controlling for a range of known confounders. Cases were all cars involved in crashes in which at least one occupant was hospitalized or killed anywhere in the Auckland region, and controls were randomly selected cars on Auckland roads. The drivers of the 571 case vehicles and 588 control vehicles completed a structured interview. Hospitalisation or death of a vehicle occupant due to car crash injury. Vehicles constructed before 1984 had significantly greater chance of being involved in an injury crash than those constructed after 1994 (odds ratio 2.88, 95% confidence interval (CI) 1.20 to 6.91), after adjustment for potential confounders. There was also a trend for increasing crash risk with each one year increase in vehicle age after adjustment for potential confounders (odds ratio 1.05, 95% CI 0.99 to 1.11; p = 0.09). This study quantifies the increased risk of car crash injury associated with older vehicle year and confirms this as an important public health issue.

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.

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.

Monoamine oxidase-B (MAO-B) inhibitors: implications for disease-modification in Parkinson’s disease

PubMed Central

2013-01-01

There is a substantial amount of evidence from experimental parkinsonian models to show the neuroprotective effects of monoamine oxidase-B (MAOB) inhibitors. They have been studied for their potential disease-modifying effects in Parkinson’s disease (PD) for over 20 years in various clinical trials. This review provides a summary of the clinical trials and discusses the implications of their results in the context of disease-modification in PD. Earlier clinical trials on selegiline were confounded by symptomatic effects of this drug. Later clinical trials on rasagiline using delayed-start design provide newer insights in disease-modification in PD but success in achieving the aims of this strategy remain elusive due to obstacles, some of which may be insurmountable. PMID:24011391

Maternal smoking during pregnancy and child outcomes: Real or spurious effect?

PubMed Central

Knopik, Valerie S.

2013-01-01

Maternal smoking during pregnancy (MSDP) is a major public health concern with clearly established consequences to both mother and newborn (e.g., low birth weight, altered cardiorespiratory responses). MSDP has also been associated with higher rates of a variety of poor cognitive and behavioral outcomes in children, including ADHD, conduct disorder, impaired learning and memory, and cognitive dysfunction. However, the evidence suggesting causal effects of MSDP for these outcomes is muddied in the existing literature due to the frequent inability to separate prenatal exposure effects from other confounding environmental and genetic factors. Carefully designed studies using genetically sensitive strategies can build upon current evidence and begin to elucidate the likely complex factors contributing to associations between MSDP and child outcomes. PMID:19142764

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.

Adaptive memory: Is the animacy effect on memory due to emotional arousal?

PubMed

Meinhardt, Martin J; Bell, Raoul; Buchner, Axel; Röer, Jan P

2018-05-07

Animate entities are often better remembered than inanimate ones. The proximal mechanisms underlying this animacy effect on recall are unclear. In two experiments, we tested whether the animacy effect is due to emotional arousal. Experiment 1 revealed that translations of the animate words used in the pioneering study of Nairne et al. (Psychological science, 24, 2099-2105, 2013) were perceived as being more arousing than translations of the inanimate words, suggesting that animacy might have been confounded with arousal in previous studies. In Experiment 2, new word lists were created in which the animate and inanimate words were matched on arousal (amongst several other dimensions), and participants were required to reproduce the animate and inanimate words in a free recall task. There was a tendency towards better memory for arousing items, but robust animacy effects were obtained even though animate and inanimate words were matched on arousal. Thus, while arousal may contribute to the animacy effect when it is not carefully controlled for, it cannot explain the memory advantage of animate items.

Using Multiple Control Groups and Matching to Address Unobserved Biases in Comparative Effectiveness Research: An Observational Study of the Effectiveness of Mental Health Parity.

PubMed

Yoon, Frank B; Huskamp, Haiden A; Busch, Alisa B; Normand, Sharon-Lise T

2011-06-21

Studies of large policy interventions typically do not involve randomization. Adjustments, such as matching, can remove the bias due to observed covariates, but residual confounding remains a concern. In this paper we introduce two analytical strategies to bolster inferences of the effectiveness of policy interventions based on observational data. First, we identify how study groups may differ and then select a second comparison group on this source of difference. Second, we match subjects using a strategy that finely balances the distributions of key categorical covariates and stochastically balances on other covariates. An observational study of the effect of parity on the severely ill subjects enrolled in the Federal Employees Health Benefits (FEHB) Program illustrates our methods.

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

Carbohydrate intake and tennis: are there benefits?

PubMed Central

Kovacs, M S

2006-01-01

Carbohydrate supplementation in prolonged aerobic exercise has been shown to be effective in improving performance and deferring fatigue. However, there is confounding evidence with regard to carbohydrate supplementation and tennis performance, which may be due to the limited number of studies on this topic. This evidence based review, using database searches of Medline and SPORTDiscus, summarises the limited relevant literature to determine if carbohydrate supplementation benefits tennis performance, and, if so, the appropriate amounts and timing. Although more research is required, it appears that it may be beneficial in tennis sessions lasting more than 90 minutes. PMID:16632561

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.

Disconcordance in Statistical Models of Bisphenol A and Chronic Disease Outcomes in NHANES 2003-08

PubMed Central

Casey, Martin F.; Neidell, Matthew

2013-01-01

Background Bisphenol A (BPA), a high production chemical commonly found in plastics, has drawn great attention from researchers due to the substance’s potential toxicity. Using data from three National Health and Nutrition Examination Survey (NHANES) cycles, we explored the consistency and robustness of BPA’s reported effects on coronary heart disease and diabetes. Methods And Findings We report the use of three different statistical models in the analysis of BPA: (1) logistic regression, (2) log-linear regression, and (3) dose-response logistic regression. In each variation, confounders were added in six blocks to account for demographics, urinary creatinine, source of BPA exposure, healthy behaviours, and phthalate exposure. Results were sensitive to the variations in functional form of our statistical models, but no single model yielded consistent results across NHANES cycles. Reported ORs were also found to be sensitive to inclusion/exclusion criteria. Further, observed effects, which were most pronounced in NHANES 2003-04, could not be explained away by confounding. Conclusions Limitations in the NHANES data and a poor understanding of the mode of action of BPA have made it difficult to develop informative statistical models. Given the sensitivity of effect estimates to functional form, researchers should report results using multiple specifications with different assumptions about BPA measurement, thus allowing for the identification of potential discrepancies in the data. PMID:24223205

The BDNF-Val66Met polymorphism modulates parental rearing effects on adult psychiatric symptoms: a community twin-based study.

PubMed

Ibarra, P; Alemany, S; Fatjó-Vilas, M; Córdova-Palomera, A; Goldberg, X; Arias, B; González-Ortega, I; González-Pinto, A; Nenadic, I; Fañanás, L

2014-06-01

To test whether firstly, different parental rearing components were associated with different dimensions of psychiatric symptoms in adulthood, secondly BDNF-Val66Met polymorphism moderated this association and thirdly, this association was due to genetic confounding. Perceived parental rearing according to Parental Bonding Instrument (PBI), psychiatric symptoms evaluated with the Brief Symptom Inventory (BSI) and the BDNF-Val66Met polymorphism were analyzed in a sample of 232 adult twins from the general population. In the whole sample, paternal care was negatively associated with depression. Maternal overprotection was positively associated with paranoid ideation, obsession-compulsion and somatization. Gene-environment interaction effects were detected between the BDNF-Val66Met polymorphism and maternal care on phobic anxiety, paternal care on hostility, maternal overprotection on somatization and paternal overprotection also in somatization. In the subsample of MZ twins, intrapair differences in maternal care were associated with anxiety, paranoid ideation and somatization. Met carriers were, in general, more sensitive to the effects of parental rearing compared to Val/Val carriers in relation to anxiety and somatization. Contra-intuitively, our findings suggest that high rates of maternal care might be of risk for Met carriers regarding anxiety. Results from analyses controlling for genetic confounding were in line with this finding. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Unemployment and subsequent depression: A mediation analysis using the parametric G-formula.

PubMed

Bijlsma, Maarten J; Tarkiainen, Lasse; Myrskylä, Mikko; Martikainen, Pekka

2017-12-01

The effects of unemployment on depression are difficult to establish because of confounding and limited understanding of the mechanisms at the population level. In particular, due to longitudinal interdependencies between exposures, mediators and outcomes, intermediate confounding is an obstacle for mediation analyses. Using longitudinal Finnish register data on socio-economic characteristics and medication purchases, we extracted individuals who entered the labor market between ages 16 and 25 in the period 1996 to 2001 and followed them until the year 2007 (n = 42,172). With the parametric G-formula we estimated the population-averaged effect on first antidepressant purchase of a simulated intervention which set all unemployed person-years to employed. In the data, 74% of person-years were employed and 8% unemployed, the rest belonging to studying or other status. In the intervention scenario, employment rose to 85% and the hazard of first antidepressant purchase decreased by 7.6%. Of this reduction 61% was mediated, operating primarily through changes in income and household status, while mediation through other health conditions was negligible. These effects were negligible for women and particularly prominent among less educated men. By taking complex interdependencies into account in a framework of observed repeated measures data, we found that eradicating unemployment raises income levels, promotes family formation, and thereby reduces antidepressant consumption at the population-level. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Pre-conception and prenatal alcohol exposure from mothers and fathers drinking and head circumference: results from the Norwegian Mother-Child Study (MoBa)

PubMed Central

Zuccolo, Luisa; DeRoo, Lisa A.; Wills, Andrew K.; Davey Smith, George; Suren, Pål; Roth, Christine; Stoltenberg, Camilla; Magnus, Per

2016-01-01

Although microcephaly is a feature of Fetal Alcohol Syndrome, it is currently unknown whether low-to-moderate prenatal alcohol exposure affects head circumference. Small magnitude associations reported in observational studies are likely to be misleading due to confounding and misclassification biases. Alternative analytical approaches such as the use of family negative controls (e.g. comparing the effects of maternal and paternal exposure) could help disentangle causal effects. We investigated the association of maternal and paternal alcohol drinking before and early in pregnancy with infant head circumference, using data from 68,244 mother-father-offspring trios from the Norwegian Mother and Child Cohort Study (MoBa) (1999–2009). In analyses adjusted for potential confounders, we found no consistent pattern of association between maternal or paternal alcohol intake before or during pregnancy and offspring head circumference modelled as a continuous outcome. However, we found higher odds of microcephaly at birth for higher paternal, but not maternal, alcohol consumption before pregnancy, and similar but weaker effect estimates for first trimester drinking. Associations with paternal drinking before pregnancy were unexpected and should be regarded as hypothesis generating, until independently replicated, although potentially important given the absence of guidelines on safe drinking levels for men in couples trying for a pregnancy. PMID:28008975

Effect of motion artifacts and their correction on near-infrared spectroscopy oscillation data: a study in healthy subjects and stroke patients.

PubMed

Selb, Juliette; Yücel, Meryem A; Phillip, Dorte; Schytz, Henrik W; Iversen, Helle K; Vangel, Mark; Ashina, Messoud; Boas, David A

2015-05-01

Functional near-infrared spectroscopy is prone to contamination by motion artifacts (MAs). Motion correction algorithms have previously been proposed and their respective performance compared for evoked rain activation studies. We study instead the effect of MAs on "oscillation" data which is at the basis of functional connectivity and autoregulation studies. We use as our metric of interest the interhemispheric correlation (IHC), the correlation coefficient between symmetrical time series of oxyhemoglobin oscillations. We show that increased motion content results in a decreased IHC. Using a set of motion-free data on which we add real MAs, we find that the best motion correction approach consists of discarding the segments of MAs following a careful approach to minimize the contamination due to band-pass filtering of data from "bad" segments spreading into adjacent "good" segments. Finally, we compare the IHC in a stroke group and in a healthy group that we artificially contaminated with the MA content of the stroke group, in order to avoid the confounding effect of increased motion incidence in the stroke patients. After motion correction, the IHC remains lower in the stroke group in the frequency band around 0.1 and 0.04 Hz, suggesting a physiological origin for the difference. We emphasize the importance of considering MAs as a confounding factor in oscillation-based functional near-infrared spectroscopy studies.

Evaluation of skeletal muscle DTI in patients with duchenne muscular dystrophy.

PubMed

Hooijmans, M T; Damon, B M; Froeling, M; Versluis, M J; Burakiewicz, J; Verschuuren, J J G M; Niks, E H; Webb, A G; Kan, H E

2015-11-01

Diffusion tensor imaging (DTI) is a popular method to assess differences in fiber organization in diseased and healthy muscle tissue. Previous work has shown that muscle DTI measurements depend on signal-to-noise ratio (SNR), %fat, and tissue T2. The goal of this study was to evaluate the potential biasing effects of these factors on skeletal muscle DTI data in patients with Duchenne Muscular Dystrophy (DMD). MR images were obtained of the right lower leg of 21 DMD patients and 12 healthy controls on a Philips 3T system. DTI measurements were combined with quantitative in-vivo measures of mean water T2, %fat and SNR to evaluate their effect on DTI parameter estimation. All outcome measures were determined within ROIs drawn for six lower leg muscles. Between group analysis, using all ROIs, revealed a significantly elevated FA in the GCL, SOL and PER muscles (p<0.05) and an increased mean diffusivity (p<0.05) and λ3 (p<0.05) in the TA muscle of DMD patients. In-vivo evaluation of the individual confounders showed behaviour in line with predictions from previous simulation work. To account for these confounders, subsequent analysis used only ROIs with SNR greater than 20. With this criterion we found significantly greater MD in the TA muscle of DMD patient (p<0.009) and λ3 in the TA and GCL muscles (p<0.001) of DMD patients, but no differences in FA. As both increased %fat and lower SNR are expected to reduce the apparent MD and λ3, these between-group differences are likely due to pathophysiology. However, the increased FA, observed when using all ROIs, likely reflects the effect of low SNR and %fat on the DTI parameter estimation. These findings suggest that measuring mean water T2, %fat and SNR is essential to ascribe changes in DTI measures to intrinsic diffusion changes or to confounding influences. Copyright © 2015 John Wiley & Sons, Ltd.

Peroxisome proliferation due to di(2-ethylhexyl) phthalate (DEHP): species differences and possible mechanisms.

PubMed Central

Elcombe, C R; Mitchell, A M

1986-01-01

The exposure of cultured rat hepatocytes to mono(2-ethylhexyl)phthalate (MEHP) for 72 hr resulted in marked induction of peroxisomal enzyme activity (beta-oxidation; cyanide-insensitive palmitoyl CoA oxidase) and concomitant increases in the number of peroxisomes. Similar treatment of cultured guinea pig, marmoset, or human hepatocytes revealed little or no effect of MEHP. In order to eliminate possible confounding influences of biotransformation, the proximate peroxisome proliferator(s) derived from MEHP have been identified. Using cultured hepatocytes these agents were found to be metabolite VI [mono(2-ethyl-5-oxohexyl) phthalate] and metabolite IX [mono(2-ethyl-5-hydroxyhexyl) phthalate]. The addition of these "active" metabolites to cultured guinea pig, marmoset, or human hepatocytes again revealed little effect upon peroxisomes or related enzyme activities (peroxisomal beta-oxidation or microsomal lauric acid hydroxylation). These studies demonstrate a marked species difference in the response of hepatocytes to MEHP-elicited peroxisome proliferation. Preliminary studies have also suggested that peroxisome proliferation due to MEHP may be due to an initial biochemical lesion of fatty acid metabolism. Images FIGURE 4. a FIGURE 4. b PMID:3104023

Dissociating distractor inhibition and episodic retrieval processes in children: No evidence for developmental deficits.

PubMed

Giesen, Carina; Weissmann, Francesca; Rothermund, Klaus

2018-02-01

It is often assumed that children show reduced or absent inhibition of distracting material due to pending cognitive maturation, although empirical findings do not provide strong support for the idea of an "inhibitory deficit" in children. Most of this evidence, however, is based on findings from the negative priming paradigm, which confounds distractor inhibition and episodic retrieval processes. To resolve this confound, we adopted a sequential distractor repetition paradigm of Giesen, Frings, and Rothermund (2012), which provides independent estimates of distractor inhibition and episodic retrieval processes. Children (aged 7-9years) and young adults (aged 18-29years) identified centrally presented target fruit stimuli among two flanking distractor fruits that were always response incompatible. Children showed both reliable distractor inhibition effects as well as robust episodic retrieval effects of distractor-response bindings. Age group comparisons suggest that processes of distractor inhibition and episodic retrieval are already present and functionally intact in children and are comparable to those of young adults. The current findings highlight that the sequential distractor repetition paradigm of Giesen et al. (2012) is a versatile tool to investigate distractor inhibition and episodic retrieval separately and in an unbiased way and is also of merit for the examination of age differences with regard to these processes. Copyright © 2017 Elsevier Inc. All rights reserved.

Differential expression analysis for RNAseq using Poisson mixed models

PubMed Central

Sun, Shiquan; Hood, Michelle; Scott, Laura; Peng, Qinke; Mukherjee, Sayan; Tung, Jenny

2017-01-01

Abstract Identifying differentially expressed (DE) genes from RNA sequencing (RNAseq) studies is among the most common analyses in genomics. However, RNAseq DE analysis presents several statistical and computational challenges, including over-dispersed read counts and, in some settings, sample non-independence. Previous count-based methods rely on simple hierarchical Poisson models (e.g. negative binomial) to model independent over-dispersion, but do not account for sample non-independence due to relatedness, population structure and/or hidden confounders. Here, we present a Poisson mixed model with two random effects terms that account for both independent over-dispersion and sample non-independence. We also develop a scalable sampling-based inference algorithm using a latent variable representation of the Poisson distribution. With simulations, we show that our method properly controls for type I error and is generally more powerful than other widely used approaches, except in small samples (n <15) with other unfavorable properties (e.g. small effect sizes). We also apply our method to three real datasets that contain related individuals, population stratification or hidden confounders. Our results show that our method increases power in all three data compared to other approaches, though the power gain is smallest in the smallest sample (n = 6). Our method is implemented in MACAU, freely available at www.xzlab.org/software.html. PMID:28369632

Bias magnification in ecologic studies: a methodological investigation

PubMed Central

Webster, Thomas F

2007-01-01

Background As ecologic studies are often inexpensive to conduct, consideration of the magnitude and direction of ecologic biases may be useful in both study design and sensitivity analysis of results. This paper examines three types of ecologic bias: confounding by group, effect measure modification by group, and non-differential exposure misclassification. Methods Bias of the risk difference on the individual and ecologic levels are compared using two-by-two tables, simple equations, and risk diagrams. Risk diagrams provide a convenient way to simultaneously display information from both levels. Results Confounding by group and effect measure modification by group act in the same direction on the individual and group levels, but have larger impact on the latter. The reduction in exposure variance caused by aggregation magnifies the individual level bias due to ignoring groups. For some studies, the magnification factor can be calculated from the ecologic data alone. Small magnification factors indicate little bias beyond that occurring at the individual level. Aggregation is also responsible for the different impacts of non-differential exposure misclassification on individual and ecologic studies. Conclusion The analytical tools developed here are useful in analyzing ecologic bias. The concept of bias magnification may be helpful in designing ecologic studies and performing sensitivity analysis of their results. PMID:17615079

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.

The confounded effects of age and exposure history in response to influenza vaccination

PubMed Central

Höpping, Ana Mosterín; McElhaney, Janet; Fonville, Judith M.; Powers, Douglas C.; Beyer, Walter E.P.; Smith, Derek J.

2016-01-01

Numerous studies have explored whether the antibody response to influenza vaccination in elderly adults is as strong as it is in young adults. Results vary, but tend to indicate lower post-vaccination titers (antibody levels) in the elderly, supporting the concept of immunosenescence – the weakening of the immunological response related to age. Because the elderly in such studies typically have been vaccinated against influenza before enrollment, a confounding of effects occurs between age, and previous exposures, as a potential extrinsic reason for immunosenescence. We conducted a four-year study of serial annual immunizations with inactivated trivalent influenza vaccines in 136 young adults (16 to 39 years) and 122 elderly adults (62 to 92 years). Compared to data sets of previously published studies, which were designed to investigate the effect of age, this detailed longitudinal study with multiple vaccinations allowed us to also study the effect of prior vaccination history on the response to a vaccine. In response to the first vaccination, young adults produced higher post-vaccination titers, accounting for pre-vaccination titers, than elderly adults. However, upon subsequent vaccinations the difference in response to vaccination between the young and elderly age groups declined rapidly. Although age is an important factor when modeling the outcome of the first vaccination, this term lost its relevance with successive vaccinations. In fact, when we examined the data with the assumption that the elderly group had received (on average) as few as two vaccinations prior to our study, the difference due to age disappeared. Our analyses therefore show that the initial difference between the two age groups in their response to vaccination may not be uniquely explained by immunosenescence due to ageing of the immune system, but could equally be the result of the different pre-study vaccination and infection histories in the elderly. PMID:26667611

The confounded effects of age and exposure history in response to influenza vaccination.

PubMed

Mosterín Höpping, Ana; McElhaney, Janet; Fonville, Judith M; Powers, Douglas C; Beyer, Walter E P; Smith, Derek J

2016-01-20

Numerous studies have explored whether the antibody response to influenza vaccination in elderly adults is as strong as it is in young adults. Results vary, but tend to indicate lower post-vaccination titers (antibody levels) in the elderly, supporting the concept of immunosenescence-the weakening of the immunological response related to age. Because the elderly in such studies typically have been vaccinated against influenza before enrollment, a confounding of effects occurs between age, and previous exposures, as a potential extrinsic reason for immunosenescence. We conducted a four-year study of serial annual immunizations with inactivated trivalent influenza vaccines in 136 young adults (16 to 39 years) and 122 elderly adults (62 to 92 years). Compared to data sets of previously published studies, which were designed to investigate the effect of age, this detailed longitudinal study with multiple vaccinations allowed us to also study the effect of prior vaccination history on the response to a vaccine. In response to the first vaccination, young adults produced higher post-vaccination titers, accounting for pre-vaccination titers, than elderly adults. However, upon subsequent vaccinations the difference in response to vaccination between the young and elderly age groups declined rapidly. Although age is an important factor when modeling the outcome of the first vaccination, this term lost its relevance with successive vaccinations. In fact, when we examined the data with the assumption that the elderly group had received (on average) as few as two vaccinations prior to our study, the difference due to age disappeared. Our analyses therefore show that the initial difference between the two age groups in their response to vaccination may not be uniquely explained by immunosenescence due to ageing of the immune system, but could equally be the result of the different pre-study vaccination and infection histories in the elderly. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Use of intracranial and ocular thermography before and after arteriovenous malformation excision

NASA Astrophysics Data System (ADS)

Hwang, Peter Y. K.; Lewis, Philip M.; Maller, Jerome J.

2014-11-01

Excision of arteriovenous malformations (AVMs) is known to carry a risk of postoperative hemorrhage, postulated to be the result of normal perfusion pressure breakthrough. It is also possible that AVMs may cause a steal effect, reducing perfusion in nearby vessels. There is currently no simple method of visualizing the presence or absence of steal effect intraoperatively. We hypothesized that the infrared thermographic (heat sensitive) imaging of perilesional brain may be useful for detecting reduced perfusion due to steal. Moreover, we hypothesized that if steal effect was present, it could impact on ocular perfusion and thereby temperature. Our objective was, therefore, to investigate whether perilesional cortical and ocular temperature (OT) may be a marker of steal effect. We intraoperatively acquired conventional and thermal images of the surgical field and eyes bilaterally, pre- and post-excisions of a large left hemisphere AVM. We found OT asymmetry preoperatively, which was absent after the AVM was excised. Intraoperative thermal images showed an increase of perilesional temperature, although this could be confounded by generalized changes in cortical perfusion due to anesthetics or surgery.

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.

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.

Chromosome 9p21 In Ischemic Stroke: Population Structure and Meta-Analysis

PubMed Central

Anderson, CD; Biffi, A; Rost, NS; Cortellini, L; Furie, KL; Rosand, J

2011-01-01

Background and Purpose Sequence variants on chromosome 9p21.3 are implicated in coronary artery disease (CAD) and myocardial infarction (MI), but studies in ischemic stroke have produced inconsistent results. We investigated whether these conflicting findings were due to false positive studies confounded by population stratification, or false negative studies that failed to account for effects specific to certain stroke subtypes. Methods After assessing for population stratification at 9p21.3 using genome-wide data, we meta-analyzed 8 ischemic stroke studies. This analysis focused on two single nucleotide polymorphisms (SNPs), rs1537378 and rs10757278, as these variants are in strong linkage disequilibrium with most SNPs analyzed in prior studies of the region. Results Principal component analysis of the genome-wide data showed no evidence of population stratification at that locus. Meta-analysis confirmed that both rs1537378 and rs10757278 are risk factors for ischemic stroke (odds ratios 1.09, [p = 0.0014], and 1.11, [p = 0.001] respectively). Subtype analysis revealed a substantial increase in the effect of each SNP for risk of large artery (LA) stroke, achieving an effect size similar to that seen in CAD/MI. Conclusions Variants on 9p21.3 are associated with ischemic stroke, and restriction of analysis to LA stroke increases effect size towards that observed in prior association studies of CAD/MI. Previous inconsistent findings are best explained by this subtype-specificity rather than any unmeasured confounding by population stratification. PMID:20395606

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.

Inverse probability weighting in STI/HIV prevention research: methods for evaluating social and community interventions

PubMed Central

Lippman, Sheri A.; Shade, Starley B.; Hubbard, Alan E.

2011-01-01

Background Intervention effects estimated from non-randomized intervention studies are plagued by biases, yet social or structural intervention studies are rarely randomized. There are underutilized statistical methods available to mitigate biases due to self-selection, missing data, and confounding in longitudinal, observational data permitting estimation of causal effects. We demonstrate the use of Inverse Probability Weighting (IPW) to evaluate the effect of participating in a combined clinical and social STI/HIV prevention intervention on reduction of incident chlamydia and gonorrhea infections among sex workers in Brazil. Methods We demonstrate the step-by-step use of IPW, including presentation of the theoretical background, data set up, model selection for weighting, application of weights, estimation of effects using varied modeling procedures, and discussion of assumptions for use of IPW. Results 420 sex workers contributed data on 840 incident chlamydia and gonorrhea infections. Participators were compared to non-participators following application of inverse probability weights to correct for differences in covariate patterns between exposed and unexposed participants and between those who remained in the intervention and those who were lost-to-follow-up. Estimators using four model selection procedures provided estimates of intervention effect between odds ratio (OR) .43 (95% CI:.22-.85) and .53 (95% CI:.26-1.1). Conclusions After correcting for selection bias, loss-to-follow-up, and confounding, our analysis suggests a protective effect of participating in the Encontros intervention. Evaluations of behavioral, social, and multi-level interventions to prevent STI can benefit by introduction of weighting methods such as IPW. PMID:20375927

Comparing consistency of R2* and T2*-weighted BOLD analysis of resting state fetal fMRI

NASA Astrophysics Data System (ADS)

Seshamani, Sharmishtaa; Blazejewska, Anna I.; Gatenby, Christopher; Mckown, Susan; Caucutt, Jason; Dighe, Manjiri; Studholme, Colin

2015-03-01

Understanding when and how resting state brain functional activity begins in the human brain is an increasing area of interest in both basic neuroscience and in the clinical evaluation of the brain during pregnancy and after premature birth. Although fMRI studies have been carried out on pregnant women since the 1990's, reliable mapping of brain function in utero is an extremely challenging problem due to the unconstrained fetal head motion. Recent studies have employed scrubbing to exclude parts of the time series and whole subjects from studies in order to control the confounds of motion. Fundamentally, even after correction of the location of signals due to motion, signal intensity variations are a fundamental limitation, due to coil sensitivity and spin history effects. An alternative technique is to use a more parametric MRI signal derived from multiple echoes that provides a level of independence from basic MRI signal variation. Here we examine the use of R2* mapping combined with slice based multi echo geometric distortion correction for in-utero studies. The challenges for R2* mapping arise from the relatively low signal strength of in-utero data. In this paper we focus on comparing activation detection in-utero using T2W and R2* approaches. We make use a subset of studies with relatively limited motion to compare the activation patterns without the additional confound of significant motion. Results at different gestational ages indicate comparable agreement in many activation patterns when limited motion is present, and the detection of some additional networks in the R2* data, not seen in the T2W results.

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.

Reversed association between aldosterone and mortality in hemodialysis patients: Role of volume overload.

PubMed

Hung, Szu-Chun; Tarng, Der-Cherng

2016-07-01

The role of aldosterone has expanded from its genomic effects that involve renal sodium transport to nongenomic effects such as cardiac and renal fibrosis. Elevated aldosterone levels are associated with increased mortality in the general population. However, the association is reversed in patients with end-stage renal disease on maintenance hemodialysis. We have shown that the inverse association between aldosterone and mortality in hemodialysis patients is due to the confounding effect of volume overload. Volume overload, which is prevalent in patients with chronic kidney disease, is associated with both lower aldosterone concentrations and higher mortality. Our findings support salt and water restriction and treatment of hyperaldosteronemia in hemodialysis patients who have achieved strict volume control. Copyright © 2016 Elsevier Inc. 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.

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.

Hepatitis E, Helicobacter pylori, and gastrointestinal symptoms in workers exposed to waste water

PubMed Central

Jeggli, S; Steiner, D; Joller, H; Tschopp, A; Steffen, R; Hotz, P

2004-01-01

Background: Workers exposed to sewage may have an increased risk of infection by Helicobacter pylori and hepatitis E virus (HEV). Aims: To assess the prevalence of clinical hepatitis E (HE) and peptic ulcer disease as well as the seroprevalence of antibodies to H pylori and HEV in workers with and without sewage exposure and to look for symptoms due to exposure to endotoxin. Methods: In the first year of a prospective cohort study 349 sewage exposed workers and 429 municipal manual workers (participation: 61%) underwent a complete medical examination. Travelling to endemic areas, socioeconomic level, age, country in which childhood was spent, and number of siblings were considered as the main confounding factors. Results: Peptic ulcer disease and clinical HE did not occur more often in workers exposed to sewage. Prevalence of antibodies to HEV was 3.3% and overall prevalence of IgG antibodies to H pylori was 42% with large differences between subgroups. Logistic regression did not show an increased risk of seropositivity or antibodies to parietal cells in sewage exposed workers, but disentangling the effect of exposure from that of confounders was extremely difficult. No increase of symptoms due to exposure to endotoxin was found in sewage workers, with the exception of diarrhoea. Conclusions: No clear increased risk of infection by H pylori or by HEV in workers exposed to sewage was found in this cross-sectional study, but these results need to be confirmed by follow up. PMID:15208379

Prenatal smoking exposure and offspring stress coping in late adolescence: no causal link.

PubMed

Kuja-Halkola, Ralf; D'Onofrio, Brian M; Iliadou, Anastasia N; Långström, Niklas; Lichtenstein, Paul

2010-12-01

In utero exposure to tobacco smoking has been suggested to cause persistent alterations in cognitive functioning. We examined if mothers' smoking during pregnancy (SDP) is associated with long-term impairment in offspring stress coping and the causal mechanism behind a possible link. We used a large cohort (n = 187,106) of young males in Sweden (mean age = 18.2 years), who underwent a semi-structured psychological assessment in 1997-2006, including an evaluation of stress coping ability, as part of the compulsory military conscript examination. We compared differentially exposed siblings within nuclear families and cousins in extended families and used multilevel structural equation models to disentangle genetic from environmental contributions to the association between SDP and stress coping. SDP and offspring stress coping was moderately strongly associated when comparing unrelated individuals [regression coefficient (b) = -0.38 on a nine-point scale; 95% confidence interval (CI) -0.40 to -0.36, P < 0.0001]. In contrast, it disappeared when siblings were compared (b = 0.11; 95% CI -0.01 to 0.23, P = 0.071). This familial confounding was entirely due to genetic influences. SDP is an established risk factor for pregnancy- and birth-related complications. However, we found no long-term effect of SDP on offspring stress coping. Rather, the observed association was due to familial confounding of genetic origin; women prone to SDP also transmit genes to their children that are associated with poorer coping with stress.

Basic characteristics of simultaneous color contrast revisited.

PubMed

Ekroll, Vebjørn; Faul, Franz

2012-10-01

In this article, we present evidence supporting the hypothesis that the local mechanism of simultaneous color contrast is the same as the mechanism responsible for the crispening effect and the gamut expansion effect. A theoretically important corollary of this hypothesis is that the basic characteristics of simultaneous contrast are at odds with traditional laws. First, this hypothesis implies that the direction of the simultaneous contrast effect in color space is given by the vector from surround to target and not--as traditionally assumed--by the hue complementary to that of the surround. Second, it implies that the size of the simultaneous contrast effect depends on the difference between the target and surround colors in a way that challenges Kirschmann's fourth law. The widespread belief in the traditional laws, we argue, is due to the confounding influence of temporal adaptation.

Effect of cannabis smoking on lung function and respiratory symptoms: a structured literature review

PubMed Central

Ribeiro, Luis IG; Ind, Philip W

2016-01-01

As cannabis use increases, physicians need to be familiar with the effects of both cannabis and tobacco on the lungs. However, there have been very few long-term studies of cannabis smoking, mostly due to legality issues and the confounding effects of tobacco. It was previously thought that cannabis and tobacco had similar long-term effects as both cause chronic bronchitis. However, recent large studies have shown that, instead of reducing forced expiratory volume in 1 s and forced vital capacity (FVC), marijuana smoking is associated with increased FVC. The cause of this is unclear, but acute bronchodilator and anti-inflammatory effects of cannabis may be relevant. Bullous lung disease, barotrauma and cannabis smoking have been recognised in case reports and small series. More work is needed to address the effects of cannabis on lung function, imaging and histological changes. PMID:27763599

Correction for Metastability in the Quantification of PID in Thin-film Module Testing: Preprint

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

Hacke, Peter L; Johnston, Steven; Spataru, Sergiu

A fundamental change in the analysis for the accelerated stress testing of thin-film modules is proposed, whereby power changes due to metastability and other effects that may occur due to the thermal history are removed from the power measurement that we obtain as a function of the applied stress factor. The power of reference modules normalized to an initial state - undergoing the same thermal and light- exposure history but without the applied stress factor such as humidity or voltage bias - is subtracted from that of the stressed modules. For better understanding and appropriate application in standardized tests, themore » method is demonstrated and discussed for potential-induced degradation testing in view of the parallel-occurring but unrelated physical mechanisms that can lead to confounding power changes in the module.« less

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.

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).

[Elements of a clinical differential diagnosis between Asperger syndrome and the schizoid/paranoid personality].

PubMed

Mottron, Laurent; Soulières, Isabelle; Ménard, Edith

2007-01-01

Individuals with Asperger syndrome may, when exposed to hostility (e.g. bullying at school or at work), develop hostile ideas against their social environment, sometimes leading to aggression. These ideas and acts may be confounded with those arising from a persecutory state in schizoid or schizotypal personality, or even schizophrenia. These entities can be confounded with Asperger syndrome due to their permanent nature, and the presence of atypical social and emotional behaviours. This paper proposes cognitive (Wechsler profile), developmental (course of hostile behaviours), discursive (qualitative features of discourse reporting hostile thoughts), which may contribute to differential diagnosis in the presence of hostile thoughts and behaviours. Consequences for case management are also reported.

Paternal and maternal alcohol abuse and offspring mental distress in the general population: the Nord-Trøndelag health study

PubMed Central

2012-01-01

Background The degree to which parental alcohol abuse is a risk factor for offspring mental distress is unclear, due to conflicting results of previous research. The inconsistencies in previous findings may be related to sample characteristics and lack of control of confounding or moderating factors. One such factor may be the gender of the abusing parent. Also, other factors, such as parental mental health, divorce, adolescent social network, school functioning or self-esteem, may impact the outcome. This study examines the impact of maternal and paternal alcohol abuse on adolescent mental distress, including potentially confounding, mediating or moderating effects of various variables. Methods Data from the Nord-Trøndelag Health Study (HUNT), a Norwegian population based health survey, from 4012 offspring and their parents were analyzed. Parental alcohol abuse was measured by numerical consumption indicators and CAGE, whereas offspring mental distress was measured by SCL-5, an abbreviated instrument tapping symptoms of anxiety and depression. Statistical method was analysis of variance. Results Maternal alcohol abuse was related to offspring mental distress, whereas no effect could be shown of paternal alcohol abuse. Effects of maternal alcohol abuse was partly mediated by parental mental distress, offspring social network and school functioning. However, all effects were relatively small. Conclusions The results indicate graver consequences for offspring of alcohol abusing mothers compared to offspring of alcohol abusing fathers. However, small effect sizes suggest that adolescent offspring of alcohol abusing parents in general manage quite well. PMID:22708789

Assessing treatment effects in older breast cancer patients: systematic review of observational research methods.

PubMed

de Glas, N A; Kiderlen, M; de Craen, A J M; Hamaker, M E; Portielje, J E A; van de Velde, C J H; Liefers, G J; Bastiaannet, E

2015-03-01

Solid evidence of treatment effects in older women with breast cancer is lacking, as they are generally underrepresented in randomized clinical trials on which guideline recommendations are based. An alternative way to study treatment effects in older patients could be to use data from observational studies. However, using appropriate methods in analyzing observational data is a key condition in order to draw valid conclusions, as directly comparing treatments generally results in biased estimates due to confounding by indication. The aim of this systematic review was to investigate the methods that have been used in observational studies that assessed the effects of breast cancer treatment on survival, breast cancer survival and recurrence in older patients (aged 65 years and older). Studies were identified through systematic review of the literature published between January 1st 2009 and December 13th 2013 in the PubMed database and EMBASe. Finally, 31 studies fulfilled the inclusion criteria. Of these, 22 studies directly compared two treatments. Fifteen out of these 22 studies addressed the problem of confounding by indication, while seven studies did not. Nine studies used some form of instrumental variable analysis. In conclusion, the vast majority of observational studies that investigate treatment effects in older breast cancer patients compared treatments directly. These studies are therefore likely to be biased. Observational research will be essential to improve treatment and outcome of older breast cancer patients, but the use of accurate methods is essential to draw valid conclusions from this type of data. Copyright © 2015 Elsevier Ltd. All rights reserved.

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...

A comparison of two colorimetric assays, based upon Lowry and Bradford techniques, to estimate total protein in soil extracts.

PubMed

Redmile-Gordon, M A; Armenise, E; White, R P; Hirsch, P R; Goulding, K W T

2013-12-01

Soil extracts usually contain large quantities of dissolved humified organic material, typically reflected by high polyphenolic content. Since polyphenols seriously confound quantification of extracted protein, minimising this interference is important to ensure measurements are representative. Although the Bradford colorimetric assay is used routinely in soil science for rapid quantification protein in soil-extracts, it has several limitations. We therefore investigated an alternative colorimetric technique based on the Lowry assay (frequently used to measure protein and humic substances as distinct pools in microbial biofilms). The accuracies of both the Bradford assay and a modified Lowry microplate method were compared in factorial combination. Protein was quantified in soil-extracts (extracted with citrate), including standard additions of model protein (BSA) and polyphenol (Sigma H1675-2). Using the Lowry microplate assay described, no interfering effects of citrate were detected even with concentrations up to 5 times greater than are typically used to extract soil protein. Moreover, the Bradford assay was found to be highly susceptible to two simultaneous and confounding artefacts: 1) the colour development due to added protein was greatly inhibited by polyphenol concentration, and 2) substantial colour development was caused directly by the polyphenol addition. In contrast, the Lowry method enabled distinction between colour development from protein and non-protein origin, providing a more accurate quantitative analysis. These results suggest that the modified-Lowry method is a more suitable measure of extract protein (defined by standard equivalents) because it is less confounded by the high polyphenolic content which is so typical of soil extracts.

Assumption Trade-Offs When Choosing Identification Strategies for Pre-Post Treatment Effect Estimation: An Illustration of a Community-Based Intervention in Madagascar.

PubMed

Weber, Ann M; van der Laan, Mark J; Petersen, Maya L

2015-03-01

Failure (or success) in finding a statistically significant effect of a large-scale intervention may be due to choices made in the evaluation. To highlight the potential limitations and pitfalls of some common identification strategies used for estimating causal effects of community-level interventions, we apply a roadmap for causal inference to a pre-post evaluation of a national nutrition program in Madagascar. Selection into the program was non-random and strongly associated with the pre-treatment (lagged) outcome. Using structural causal models (SCM), directed acyclic graphs (DAGs) and simulated data, we illustrate that an estimand with the outcome defined as the post-treatment outcome controls for confounding by the lagged outcome but not by possible unmeasured confounders. Two separate differencing estimands (of the pre- and post-treatment outcome) have the potential to adjust for a certain type of unmeasured confounding, but introduce bias if the additional identification assumptions they rely on are not met. In order to illustrate the practical impact of choice between three common identification strategies and their corresponding estimands, we used observational data from the community nutrition program in Madagascar to estimate each of these three estimands. Specifically, we estimated the average treatment effect of the program on the community mean nutritional status of children 5 years and under and found that the estimate based on the post-treatment estimand was about a quarter of the magnitude of either of the differencing estimands (0.066 SD vs. 0.26-0.27 SD increase in mean weight-for-age z-score). Choice of estimand clearly has important implications for the interpretation of the success of the program to improve nutritional status of young children. A careful appraisal of the assumptions underlying the causal model is imperative before committing to a statistical model and progressing to estimation. However, knowledge about the data-generating process must be sufficient in order to choose the identification strategy that gets us closest to the truth.

Experimental and clinical evidence for loss of effect (tolerance) during prolonged treatment with antiepileptic drugs.

PubMed

Löscher, Wolfgang; Schmidt, Dieter

2006-08-01

Development of tolerance (i.e., the reduction in response to a drug after repeated administration) is an adaptive response of the body to prolonged exposure to the drug, and tolerance to antiepileptic drugs (AEDs) is no exception. Tolerance develops to some drug effects much more rapidly than to others. The extent of tolerance depends on the drug and individual (genetic?) factors. Tolerance may lead to attenuation of side effects but also to loss of efficacy of AEDs and is reversible after discontinuation of drug treatment. Different experimental approaches are used to study tolerance in laboratory animals. Development of tolerance depends on the experimental model, drug, drug dosage, and duration of treatment, so that a battery of experimental protocols is needed to evaluate fully whether tolerance to effect occurs. Two major types of tolerance are known. Pharmacokinetic (metabolic) tolerance, due to induction of AED-metabolizing enzymes has been shown for most first-generation AEDs, and is easy to overcome by increasing dosage. Pharmacodynamic (functional) tolerance is due to "adaptation" of AED targets (e.g., by loss of receptor sensitivity) and has been shown experimentally for all AEDs that lose activity during prolonged treatment. Functional tolerance may lead to complete loss of AED activity and cross-tolerance to other AEDs. Convincing experimental evidence indicates that almost all first-, second-, and third-generation AEDs lose their antiepileptic activity during prolonged treatment, although to a different extent. Because of diverse confounding factors, detecting tolerance in patients with epilepsy is more difficult but can be done with careful assessment of decline during long-term individual patient response. After excluding confounding factors, tolerance to antiepileptic effect for most modern and old AEDs can be shown in small subgroups of responders by assessing individual or group response. Development of tolerance to the antiepileptic activity of an AED may be an important reason for failure of drug treatment. Knowledge of tolerance to AED effects as a mechanism of drug resistance in previous responders is important for patients, physicians, and scientists.

Saturated Fats and Cardiovascular Disease: Interpretations Not as Simple as They Once Were.

PubMed

Bier, Dennis M

2016-09-09

Historically, the so-called "lipid hypothesis" has focused on the detrimental role of saturated fats per se in enhancing the risks of cardiovascular disease. Recently, a body of new information and systematic analyses of available data have questioned simple interpretation of the relationship of dietary saturated fats and of individual saturated fatty acids to CVD risk. Thus, current assessments of risks due to dietary fat consumption that emphasize the confounding nature of the dietary macronutrients substituted for dietary saturated fats and give broader recognition to the effect of patterns of food intake as a whole are the most productive approach to an overall healthy diet.

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

Diffusion of multiple species with excluded-volume effects.

PubMed

Bruna, Maria; Chapman, S Jonathan

2012-11-28

Stochastic models of diffusion with excluded-volume effects are used to model many biological and physical systems at a discrete level. The average properties of the population may be described by a continuum model based on partial differential equations. In this paper we consider multiple interacting subpopulations/species and study how the inter-species competition emerges at the population level. Each individual is described as a finite-size hard core interacting particle undergoing brownian motion. The link between the discrete stochastic equations of motion and the continuum model is considered systematically using the method of matched asymptotic expansions. The system for two species leads to a nonlinear cross-diffusion system for each subpopulation, which captures the enhancement of the effective diffusion rate due to excluded-volume interactions between particles of the same species, and the diminishment due to particles of the other species. This model can explain two alternative notions of the diffusion coefficient that are often confounded, namely collective diffusion and self-diffusion. Simulations of the discrete system show good agreement with the analytic results.

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.

Pesticide exposure and stunting as independent predictors of neurobehavioral deficits in Ecuadorian school children.

PubMed

Grandjean, Philippe; Harari, Raul; Barr, Dana B; Debes, Frodi

2006-03-01

To examine possible effects on blood pressure, neurological function, and neurobehavioral tests in school-aged children with and without prenatal pesticide exposure in an area where stunting is common. In a community of Northern Ecuador with intensive floriculture and a high female employment rate, we invited 79 children attending the 2 lowest grades of a public school for clinical examinations. In addition to a thorough physical examination, we administered simple reaction time, Santa Ana dexterity test, Stanford-Binet copying, and Wechsler Intelligence Scale for Children-Revised Digit Spans forward. Maternal interview included detailed assessment of occupational history to determine pesticide exposure during pregnancy. Recent and current pesticide exposure was assessed by erythrocyte acetylcholine esterase activity and urinary excretion of organophosphate metabolites. All eligible children participated in the study, but 7 children were excluded from data analysis due to other disease or age >9 years. A total of 31 of the remaining 72 children were classified as stunted based on their height for age. Maternal occupational history revealed that 37 children had been exposed to pesticides during development. After confounder adjustment, prenatal pesticide exposure was associated with a higher systolic blood pressure than in the controls. On neurological examination, 14 exposed children and 9 controls showed > or =1 abnormalities. Of 5 neurobehavioral tests, the Stanford-Binet copying test showed a lower drawing score for copying designs in exposed children than in controls. Stunting was associated with a lower score on this test only, and both risk factors remained statistically significant in a multiple regression analysis with adjustment for demographic and social confounders. Increased excretion of dimethyl and diethyl metabolites of organophosphates was associated with increased reaction time and no other outcomes. Prenatal pesticide exposure may cause lasting neurotoxic damage and add to the adverse effects of malnutrition in developing countries. The effects differ from those due to acute pesticide exposure.

The relationship between labor unions and safety in US airlines: Is there a "union effect?"

NASA Astrophysics Data System (ADS)

Zapf, Renee Catherine

Every airline union claims to work for safety and presents anecdotes where greater airline safety has been achieved through union efforts. The effect unionization has on safety outcomes in U.S. commercial airlines, however, wasn't found to be previously tested. Studies have shown that in industries such as coal mining, retail, and construction, unionization does lead to an increase in safety. This study evaluated the safety rates of 15 major US commercial airlines to compare the difference between unionized and non-unionized airlines. These safety rates were compared based on if and how long each airline's pilots and flight attendants have been unionized, to determine if unionization had an effect on safety outcomes. The 15 airlines included in the study identified as operating most of the years between 1990 and 2013, with annual departures averaging over 130,000, available through the Bureau of Transportation Statistics. Accident and Incident information was acquired through the National Transportation Safety Board database. The number of accident and incidents divided by the total departures at each airline was used as the safety rate. Union websites provided information on unionization at the airlines. Due to the complex nature of the aviation industry, a number of confounding factors could have affected the tests, including mergers, route structures, and legislation. To help control for these confounding factors, this study was limited to airlines with a stable presence in the industry over time, which limited the number of airlines included. No significant difference was found between unionized and non-unionized airlines in this study, though the mean safety rate of unionized airlines was found be better than non-unionized airlines. This study did not take into account safety improvements that were union-backed and eventually required at all airlines, regardless of unionization. Due to the large sample size of the small population the difference in safety rate means could be indicative of greater safety in unionized airlines.

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.

Validation of a commercially available enzyme-linked immunoabsorbent assay for the quantification of human α-Synuclein in cerebrospinal fluid.

PubMed

Kruse, Niels; Mollenhauer, Brit

2015-11-01

The quantification of α-Synuclein in cerebrospinal fluid (CSF) as a biomarker has gained tremendous interest in the last years. Several commercially available immunoassays are emerging. We here describe the full validation of one commercially available ELISA assay for the quantification of α-Synuclein in human CSF (Covance alpha-Synuclein ELISA kit). The study was conducted within the BIOMARKAPD project in the European initiative Joint Program for Neurodegenerative Diseases (JPND). We investigated the effect of several pre-analytical and analytical confounders: i.e. (1) need for centrifugation of freshly drawn CSF, (2) sample stability, (3) delay of freezing, (4) volume of storage aliquots, (5) freeze/thaw cycles, (6) thawing conditions, (7) dilution linearity, (8) parallelism, (9) spike recovery, and (10) precision. None of these confounders influenced the levels of α-Synuclein in CSF significantly. We found a very high intra-assay precision. The inter-assay precision was lower than expected due to different performances of kit lots used. Overall the validated immunoassay is useful for the quantification of α-Synuclein in human CSF. Copyright © 2015 Elsevier B.V. All rights reserved.

Postoperative Adverse Events Inconsistently Improved by the World Health Organization Surgical Safety Checklist: A Systematic Literature Review of 25 Studies.

PubMed

de Jager, Elzerie; McKenna, Chloe; Bartlett, Lynne; Gunnarsson, Ronny; Ho, Yik-Hong

2016-08-01

The World Health Organization Surgical Safety Checklist (SSC) has been widely implemented in an effort to decrease surgical adverse events. This systematic literature review examined the effects of the SSC on postoperative outcomes. The review included 25 studies: two randomised controlled trials, 13 prospective and ten retrospective cohort trials. A meta-analysis was not conducted as combining observational studies of heterogeneous quality may be highly biased. The quality of the studies was largely suboptimal; only four studies had a concurrent control group, many studies were underpowered to examine specific postoperative outcomes and teamwork-training initiatives were often combined with the implementation of the checklist, confounding the results. The effects of the checklist were largely inconsistent. Postoperative complications were examined in 20 studies; complication rates significantly decreased in ten and increased in one. Eighteen studies examined postoperative mortality. Rates significantly decreased in four and increased in one. Postoperative mortality rates were not significantly decreased in any studies in developed nations, whereas they were significantly decreased in 75 % of studies conducted in developing nations. The checklist may be associated with a decrease in surgical adverse events and this effect seems to be greater in developing nations. With the observed incongruence between specific postoperative outcomes and the overall poor study designs, it is possible that many of the positive changes associated with the use of the checklist were due to temporal changes, confounding factors and publication bias.

Pulmonary function and fuel use: a population survey.

PubMed

Saha, Asim; Rao, N Mohan; Kulkarni, P K; Majumdar, P K; Saiyed, H N

2005-10-31

In the backdrop of conflicting reports (some studies reported adverse outcomes of biomass fuel use whereas few studies reported absence of any association between adverse health effect and fuel use, may be due to presence of large number of confounding variables) on the respiratory health effects of biomass fuel use, this cross sectional survey was undertaken to understand the role of fuel use on pulmonary function. This study was conducted in a village of western India involving 369 randomly selected adult subjects (165 male and 204 female). All the subjects were interviewed and were subjected to pulmonary function test. Analysis of covariance was performed to compare the levels of different pulmonary function test parameters in relation to different fuel use taking care of the role of possible confounding factors. This study showed that biomass fuel use (especially wood) is an important factor for deterioration of pulmonary function (particularly in female). FEV1 (p < .05), FEV1% (p < .01), PEFR (p < .05) and FEF(25-75) (p < .01) values were significantly lower in biomass fuel using females than nonusers. Comparison of only biomass fuel use vs. only LPG (Liquefied Petroleum Gas) use and only wood vs. only LPG use has showed that LPG is a safer fuel so far as deterioration of pulmonary function is concerned. This study observes some deterioration of pulmonary function in the male subjects also, who came from biomass fuel using families. This study concluded that traditional biomass fuels like wood have adverse effects on pulmonary function.

Quantification of confounding factors in MRI-based dose calculations as applied to prostate IMRT

NASA Astrophysics Data System (ADS)

Maspero, Matteo; Seevinck, Peter R.; Schubert, Gerald; Hoesl, Michaela A. U.; van Asselen, Bram; Viergever, Max A.; Lagendijk, Jan J. W.; Meijer, Gert J.; van den Berg, Cornelis A. T.

2017-02-01

Magnetic resonance (MR)-only radiotherapy treatment planning requires pseudo-CT (pCT) images to enable MR-based dose calculations. To verify the accuracy of MR-based dose calculations, institutions interested in introducing MR-only planning will have to compare pCT-based and computer tomography (CT)-based dose calculations. However, interpreting such comparison studies may be challenging, since potential differences arise from a range of confounding factors which are not necessarily specific to MR-only planning. Therefore, the aim of this study is to identify and quantify the contribution of factors confounding dosimetric accuracy estimation in comparison studies between CT and pCT. The following factors were distinguished: set-up and positioning differences between imaging sessions, MR-related geometric inaccuracy, pCT generation, use of specific calibration curves to convert pCT into electron density information, and registration errors. The study comprised fourteen prostate cancer patients who underwent CT/MRI-based treatment planning. To enable pCT generation, a commercial solution (MRCAT, Philips Healthcare, Vantaa, Finland) was adopted. IMRT plans were calculated on CT (gold standard) and pCTs. Dose difference maps in a high dose region (CTV) and in the body volume were evaluated, and the contribution to dose errors of possible confounding factors was individually quantified. We found that the largest confounding factor leading to dose difference was the use of different calibration curves to convert pCT and CT into electron density (0.7%). The second largest factor was the pCT generation which resulted in pCT stratified into a fixed number of tissue classes (0.16%). Inter-scan differences due to patient repositioning, MR-related geometric inaccuracy, and registration errors did not significantly contribute to dose differences (0.01%). The proposed approach successfully identified and quantified the factors confounding accurate MRI-based dose calculation in the prostate. This study will be valuable for institutions interested in introducing MR-only dose planning in their clinical practice.

Depression or anxiety in adult twins is associated with asthma diagnosis but not with offspring asthma.

PubMed

Tedner, S G; Lundholm, C; Olsson, H; Almqvist, C

2016-06-01

Asthma is common in both children and adults in the Western world, just like anxiety and depression. While some research has revealed that these diseases might share important environmental and pathophysiological aspects, the exact mechanisms still remain unclear. To study the correlation firstly between depression or anxiety and asthma diagnosis in adult twins and secondly the association between parental depression or anxiety and offspring asthma in children of twins. In total, 24 685 adult twins aged 20-47 years were interviewed or completed a Web-based questionnaire and their children were identified through the Multi-Generation Register. Asthma diagnosis was obtained from the Patient Register and the Prescribed Drug Register. Assessment of depression and anxiety was obtained from questionnaires using Center for Epidemiologic Studies Depression Scale (CES-D), major depression and generalized anxiety disorder (GAD) from DSM-IV. The association between depression or anxiety and asthma was analyzed with logistic regression adjusting for confounders in twins and offspring. To address genetic and familial environmental confounding, we performed a cotwin analysis using disease-discordant twin pairs. We found an association between asthma and CES-D, major depression and GAD, for example adjusted OR for major depression and register-based asthma 1.56 (1.36-1.79). Most of the point estimates remained in the co-twin control analysis, indicating that the association was likely not due to genetic or familial environmental factors. There was no association between parental depression and/or anxiety and asthma diagnosis in the offspring which implies lack of genetic confounding. We found an association between own asthma diagnosis and anxiety or depression, but not with offspring asthma. Our results indicate that the associations were not due to confounding from genes or environment shared by the twins. © 2016 John Wiley & Sons Ltd.

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…

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.

Differential expression analysis for RNAseq using Poisson mixed models.

PubMed

Sun, Shiquan; Hood, Michelle; Scott, Laura; Peng, Qinke; Mukherjee, Sayan; Tung, Jenny; Zhou, Xiang

2017-06-20

Identifying differentially expressed (DE) genes from RNA sequencing (RNAseq) studies is among the most common analyses in genomics. However, RNAseq DE analysis presents several statistical and computational challenges, including over-dispersed read counts and, in some settings, sample non-independence. Previous count-based methods rely on simple hierarchical Poisson models (e.g. negative binomial) to model independent over-dispersion, but do not account for sample non-independence due to relatedness, population structure and/or hidden confounders. Here, we present a Poisson mixed model with two random effects terms that account for both independent over-dispersion and sample non-independence. We also develop a scalable sampling-based inference algorithm using a latent variable representation of the Poisson distribution. With simulations, we show that our method properly controls for type I error and is generally more powerful than other widely used approaches, except in small samples (n <15) with other unfavorable properties (e.g. small effect sizes). We also apply our method to three real datasets that contain related individuals, population stratification or hidden confounders. Our results show that our method increases power in all three data compared to other approaches, though the power gain is smallest in the smallest sample (n = 6). Our method is implemented in MACAU, freely available at www.xzlab.org/software.html. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

A Genetically Informed Study of Associations between Family Functioning and Child Psychosocial Adjustment

ERIC Educational Resources Information Center

Schermerhorn, Alice C.; D'Onofrio, Brian M.; Turkheimer, Eric; Ganiban, Jody M.; Spotts, Erica L.; Lichtenstein, Paul; Reiss, David; Neiderhiser, Jenae M.

2011-01-01

Research has documented associations between family functioning and offspring psychosocial adjustment, but questions remain regarding whether these associations are partly due to confounding genetic factors and other environmental factors. The current study used a genetically informed approach, the Children of Twins design, to explore the…

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

Who really gets strep sore throat? Confounding and effect modification of a time-varying exposure on recurrent events.

PubMed

Follmann, Dean; Huang, Chiung-Yu; Gabriel, Erin

2016-10-30

Unmeasured confounding is the fundamental obstacle to drawing causal conclusions about the impact of an intervention from observational data. Typically, covariates are measured to eliminate or ameliorate confounding, but they may be insufficient or unavailable. In the special setting where a transient intervention or exposure varies over time within each individual and confounding is time constant, a different tack is possible. The key idea is to condition on either the overall outcome or the proportion of time in the intervention. These measures can eliminate the unmeasured confounding either by conditioning or by use of a proxy covariate. We evaluate existing methods and develop new models from which causal conclusions can be drawn from such observational data even if no baseline covariates are measured. Our motivation for this work was to determine the causal effect of Streptococcus bacteria in the throat on pharyngitis (sore throat) in Indian schoolchildren. Using our models, we show that existing methods can be badly biased and that sick children who are rarely colonized have a high probability that the Streptococcus bacteria are causing their disease. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Economic downturns and suicide mortality in the USA, 1980-2010: observational study.

PubMed

Harper, Sam; Charters, Thomas J; Strumpf, Erin C; Galea, Sandro; Nandi, Arijit

2015-06-01

Several studies have suggested strong associations between economic downturns and suicide mortality, but are at risk of bias due to unmeasured confounding. The rationale for our study was to provide more robust evidence by using a quasi-experimental design. We analysed 955,561 suicides occurring in the USA from 1980 to 2010 and used a broad index of economic activity in each US state to measure economic conditions. We used a quasi-experimental, fixed-effects design and we also assessed whether the effects were heterogeneous by demographic group and during periods of official recession. After accounting for secular trends, seasonality and unmeasured fixed characteristics of states, we found that an economic downturn similar in magnitude to the 2007 Great Recession increased suicide mortality by 0.14 deaths per 100,000 population [95% confidence interval (CI) 0.00, 0.28] or around 350 deaths. Effects were stronger for men (0.28, 95% CI 0.07, 0.49) than women and for those with less than 12 years of education (1.22 95% CI 0.83, 1.60) compared with more than 12 years of education. The overall effect did not differ for recessionary (0.11, 95% CI -0.02, 0.25) vs non-recessionary periods (0.15, 95% CI 0.01, 0.29). The main study limitation is the potential for misclassified death certificates and we cannot definitively rule out unmeasured confounding. We found limited evidence of a strong, population-wide detrimental effect of economic downturns on suicide mortality. The overall effect hides considerable heterogeneity by gender, socioeconomic position and time period. © The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

Effort--reward imbalance and medically certified absence for mental health problems: a prospective study of white-collar workers.

PubMed

Ndjaboué, R; Brisson, C; Vézina, M; Blanchette, C; Bourbonnais, R

2014-01-01

Little is known about the effects of psychosocial work factors on objectively assessed mental health problems leading to medically certified absence. Only one study has evaluated the prospective effects of effort-reward imbalance (ERI) at work with regards to this outcome. The present study aimed to evaluate the effects of ERI on the incidence of medically certified absence for mental health problems. The study included 2086 white-collar workers (63.3% women) employed in public organisations in Quebec city. Participants were followed over a 9-year period. Medical absences from work were collected from employers' files and psychosocial factors were measured using the ERI questionnaire. Cox regression models were used to estimate the incidence of certified sickness absence due to mental health problems that lasted 5 workdays or more, while controlling for confounders. Workers exposed to ERI had a higher risk of a first spell of medically certified absence for mental health problems (HR=1.38, 95% CI 1.08 to 1.76) compared with unexposed workers. Low reward was significantly associated with a high risk among men (HR=2.80, 95% CI 1.34 to 5.89) but not in women. (HR=1.24, 95% CI 0.90 to 1.73). Effort at work had no effect on certified absence. All these effects were adjusted for potential confounders. ERI and low reward at work were prospectively associated with medically certified absence for mental health problems. These effects seem to differ by gender. Primary prevention that is aimed at reducing these stressors should be considered to help reduce the incidence of such severe mental health problems.

Economic downturns and suicide mortality in the USA, 1980–2010: observational study

PubMed Central

Harper, Sam; Charters, Thomas J; Strumpf, Erin C; Galea, Sandro; Nandi, Arijit

2015-01-01

Background: Several studies have suggested strong associations between economic downturns and suicide mortality, but are at risk of bias due to unmeasured confounding. The rationale for our study was to provide more robust evidence by using a quasi-experimental design. Methods: We analysed 955 561 suicides occurring in the USA from 1980 to 2010 and used a broad index of economic activity in each US state to measure economic conditions. We used a quasi-experimental, fixed-effects design and we also assessed whether the effects were heterogeneous by demographic group and during periods of official recession. Results: After accounting for secular trends, seasonality and unmeasured fixed characteristics of states, we found that an economic downturn similar in magnitude to the 2007 Great Recession increased suicide mortality by 0.14 deaths per 100 000 population [95% confidence interval (CI) 0.00, 0.28] or around 350 deaths. Effects were stronger for men (0.28, 95% CI 0.07, 0.49) than women and for those with less than 12 years of education (1.22 95% CI 0.83, 1.60) compared with more than 12 years of education. The overall effect did not differ for recessionary (0.11, 95% CI −0.02, 0.25) vs non-recessionary periods (0.15, 95% CI 0.01, 0.29). The main study limitation is the potential for misclassified death certificates and we cannot definitively rule out unmeasured confounding. Conclusions: We found limited evidence of a strong, population-wide detrimental effect of economic downturns on suicide mortality. The overall effect hides considerable heterogeneity by gender, socioeconomic position and time period. PMID:26082407

Methodological challenges to control for immortal time bias in addressing drug effects in type 2 diabetes

PubMed Central

Yang, Xi-Lin; Huo, Xiao-Xu; Chan, Juliana CN

2015-01-01

There are multiple biases in using observational studies to examine treatment effects such as those from prevalent drug users, immortal time and drug indications. We used renin angiotensin system (RAS) inhibitors and statins as reference drugs with proven efficacies in randomized clinical trials (RCTs) and examined their effectiveness in the prospective Hong Kong Diabetes Registry using adjustment methods proposed in the literature. Using time-dependent exposures to drug treatments yielded greatly inflated hazard ratios (HR) regarding the treatment effects of these drugs for cardiovascular disease (CVD) in type 2 diabetes. These errors were probably due to changing indications to use these drugs during follow up periods, especially at the time of drug commencement making time-dependent analysis extremely problematic. Using time-fixed analysis with exclusion of immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of RAS inhibitors for CVD was comparable to that in RCT. The result supported the use of the Registry for performing pharmacoepidemiological analysis which revealed an attenuated low low-density lipoprotein cholesterol related cancer risk with RAS inhibitors. On the other hand, time-fixed analysis with including immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of statins for CVD was similar to that in the RCT. Our results highlight the complexity and difficulty in removing these biases. We call for validations of the methods to cope with immortal time and drug use indications before applying them to particular research questions, so to avoid making erroneous conclusions. PMID:26413484

Methodological challenges to control for immortal time bias in addressing drug effects in type 2 diabetes.

PubMed

Yang, Xi-Lin; Huo, Xiao-Xu; Chan, Juliana Cn

2015-09-26

There are multiple biases in using observational studies to examine treatment effects such as those from prevalent drug users, immortal time and drug indications. We used renin angiotensin system (RAS) inhibitors and statins as reference drugs with proven efficacies in randomized clinical trials (RCTs) and examined their effectiveness in the prospective Hong Kong Diabetes Registry using adjustment methods proposed in the literature. Using time-dependent exposures to drug treatments yielded greatly inflated hazard ratios (HR) regarding the treatment effects of these drugs for cardiovascular disease (CVD) in type 2 diabetes. These errors were probably due to changing indications to use these drugs during follow up periods, especially at the time of drug commencement making time-dependent analysis extremely problematic. Using time-fixed analysis with exclusion of immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of RAS inhibitors for CVD was comparable to that in RCT. The result supported the use of the Registry for performing pharmacoepidemiological analysis which revealed an attenuated low low-density lipoprotein cholesterol related cancer risk with RAS inhibitors. On the other hand, time-fixed analysis with including immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of statins for CVD was similar to that in the RCT. Our results highlight the complexity and difficulty in removing these biases. We call for validations of the methods to cope with immortal time and drug use indications before applying them to particular research questions, so to avoid making erroneous conclusions.

Marijuana use and car crash injury.

PubMed

Blows, Stephanie; Ivers, Rebecca Q; Connor, Jennie; Ameratunga, Shanthi; Woodward, Mark; Norton, Robyn

2005-05-01

To investigate the relationship between marijuana use prior to driving, habitual marijuana use and car crash injury. Population based case-control study in Auckland, New Zealand. Case vehicles were all cars involved in crashes in which at least one occupant was hospitalized or killed anywhere in the Auckland region, and control vehicles were a random sample of cars driving on Auckland roads. The drivers of 571 case and 588 control vehicles completed a structured interview. Self reported marijuana use in the 3 hours prior to the crash/survey and habitual marijuana use over the previous 12 months were recorded, along with a range of other variables potentially related to crash risk. The main outcome measure was hospitalization or death of a vehicle occupant due to car crash injury. Acute marijuana use was significantly associated with car crash injury, after controlling for the confounders age, gender, ethnicity, education level, passenger carriage, driving exposure and time of day (OR 3.9, 95% CI 1.2-12.9). However, after adjustment for these confounders plus other risky driving at the time of the crash (blood alcohol concentration, seat-belt use, travelling speed and sleepiness score), the effect of acute marijuana intake was no longer significant (OR 0.8, 95% CI 0.2-3.3). There was a strong significant association between habitual use and car crash injury after adjustment for all the above confounders plus acute use prior to driving (OR 9.5, 95% CI 2.8-32.3). This population-based case-control study indicates that habitual use of marijuana is strongly associated with car crash injury. The nature of the relationship between marijuana use and risk-taking is unclear and needs further research. The prevalence of marijuana use in this driving population was low, and acute use was associated with habitual marijuana use, suggesting that intervention strategies may be more effective if they are targeted towards high use groups.

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.

Gain-Loss Framing and Choice: Separating Outcome Formulations from Descriptor Formulations.

PubMed

Mandel, David R.

2001-05-01

This article reexamines the assumptions underlying the disease problem used by Tversky and Kahneman (1981) to illustrate gain-loss formulation effects. It is argued that their reported effect may have been due to asymmetries in the ambiguity of the sure and risky prospects and to the entanglement of two distinct types of formulation manipulations: one having to do with the expected outcomes that are made explicit (positive vs negative) and the other having to do with the descriptors used to convey the relevant expected outcomes (lives saved/not saved vs lives lost/not lost). Two experiments using a formally equivalent problem in which these confounds were eliminated revealed no significant predictive effect of either descriptor or outcomes frames on choice, although a marginally significant framing effect was obtained in Experiment 1 when the signs of the two framing manipulations were congruent. Implications for prospect theory are discussed. Copyright 2001 Academic Press.

Concentrations of Water-Soluble Vitamins in Blood and Urinary Excretion in Patients with Diabetes Mellitus.

PubMed

Iwakawa, Hiromi; Nakamura, Yasuyuki; Fukui, Tomiho; Fukuwatari, Tsutomu; Ugi, Satoshi; Maegawa, Hiroshi; Doi, Yukio; Shibata, Katsumi

2016-01-01

We examined the concentrations of water-soluble vitamins in blood and urinary excretion of 22 patients with type 2 diabetes mellitus (type 2DM) and 20 healthy control participants. Macronutrient and vitamin intakes of type 2DM subjects were measured using a weighed food record method. Control participants consumed a semipurified diet for eight days. Multiple linear regression models were used to determine whether significant differences existed in vitamin concentrations in blood independent of age, sex, and other confounding factors. Concentrations of vitamins B2, B6, C, niacin, and folate in blood were significantly lower in type 2DM subjects than in controls, independent of confounding factors. Renal clearances of vitamins B6, C, niacin, and folate were significantly higher in type 2DM subjects than in controls. In conclusion, concentrations of vitamins B2, B6, C, niacin, and folate in blood were significantly lower in type 2DM subjects than in controls, independent of confounding factors; based on the evidence of increased urinary clearance of these vitamins, the lower levels were likely due to impaired reabsorption processes.

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.

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

External radiation dose and cancer mortality among French nuclear workers: considering potential confounding by internal radiation exposure.

PubMed

Fournier, L; Laurent, O; Samson, E; Caër-Lorho, S; Laroche, P; Le Guen, B; Laurier, D; Leuraud, K

2016-11-01

French nuclear workers have detailed records of their occupational exposure to external radiation that have been used to examine associations with subsequent cancer mortality. However, some workers were also exposed to internal contamination by radionuclides. This study aims to assess the potential for bias due to confounding by internal contamination of estimates of associations between external radiation exposure and cancer mortality. A cohort of 59,004 workers employed for at least 1 year between 1950 and 1994 by CEA (Commissariat à l'Energie Atomique), AREVA NC, or EDF (Electricité de France) and badge-monitored for external radiation exposure were followed through 2004 to assess vital status and cause of death. A flag based on a workstation-exposure matrix defined four levels of potential for internal contamination. Standardized mortality ratios were assessed for each level of the internal contamination indicator. Poisson regression was used to quantify associations between external radiation exposure and cancer mortality, adjusting for potential internal contamination. For solid cancer, the mortality deficit tended to decrease as the levels of potential for internal contamination increased. For solid cancer and leukemia excluding chronic lymphocytic leukemia, adjusting the dose-response analysis on the internal contamination indicator did not markedly change the excess relative risk per Sievert of external radiation dose. This study suggests that in this cohort, neglecting information on internal dosimetry while studying the association between external dose and cancer mortality does not generate a substantial bias. To investigate more specifically the health effects of internal contamination, an effort is underway to estimate organ doses due to internal contamination.

Maternal pre-pregnancy obesity and childhood physical and cognitive development of children: a systematic review.

PubMed

Adane, A A; Mishra, G D; Tooth, L R

2016-11-01

Maternal obesity, usually associated with the adverse birth outcomes, has been a serious public health concern. Studies examining its effect on the physical and cognitive development of children have only recently emerged and the findings are inconsistent. This review aimed to systematically examine the role of maternal obesity on children's physical and cognitive development using the available evidence. The CINAHL, EMBASE, PSYCINFO, PUBMED and SCOPUS databases were searched. Studies addressing children's (⩽12 years) physical and cognitive development as outcome and maternal pre-pregnancy body mass index as an exposure were included. Data were extracted and evaluated for quality by two independent reviewers. A total of 17 articles were eligible for this systematic review; 10 of them were birth cohorts from the USA. Nine of the 14 studies supported an adverse association between maternal pre-pregnancy obesity and childhood cognitive development. A few studies also demonstrated a negative association between the maternal obesity and gross motor function in children (5 of 10), but not with fine motor function (none out of five studies). Whether the observed negative association between the maternal obesity and children's cognitive and gross motor abilities is casual or due to residual confounding effects is unclear. The current evidence is based on a limited number of studies with heterogeneous measurement scales and obesity definition. From the available evidence, it seems that exposure to maternal pre-pregnancy obesity in the intrauterine environment has a detrimental effect on children's cognitive development. However, evidence of the association between the maternal obesity and physical development of children is too scarce to offer a conclusion. More research work is required to delineate the intrauterine effect of the maternal obesity from the residual confounding effects.

Reproductive and Developmental Toxicity of Formaldehyde: A Systematic Review

PubMed Central

Duong, Anh; Steinmaus, Craig; McHale, Cliona M.; Vaughan, Charles P.; Zhang, Luoping

2011-01-01

Formaldehyde, the recently classified carcinogen and ubiquitous environmental contaminant, has long been suspected of causing adverse reproductive and developmental effects, but previous reviews were inconclusive, due in part, to limitations in the design of many of the human population studies. In the current review, we systematically evaluated evidence of an association between formaldehyde exposure and adverse reproductive and developmental effects, in human populations and in vivo animal studies, in the peer-reviewed literature. The mostly retrospective human studies provided evidence of an association of maternal exposure with adverse reproductive and developmental effects. Further assessment of this association by meta-analysis revealed an increased risk of spontaneous abortion (1.76, 95% CI 1.20–2.59, p=0.002) and of all adverse pregnancy outcomes combined (1.54, 95% CI 1.27–1.88, p<0.001), in formaldehyde-exposed women, although differential recall, selection bias, or confounding cannot be ruled out. Evaluation of the animal studies including all routes of exposure, doses and dosing regimens studied, suggested positive associations between formaldehyde exposure and reproductive toxicity, mostly in males. Potential mechanisms underlying formaldehyde-induced reproductive and developmental toxicities, including chromosome and DNA damage (genotoxicity), oxidative stress, altered level and/or function of enzymes, hormones and proteins, apoptosis, toxicogenomic and epigenomic effects (such as DNA methylation), were identified. To clarify these associations, well-designed molecular epidemiologic studies, that include quantitative exposure assessment and diminish confounding factors, should examine both reproductive and developmental outcomes associated with exposure in males and females. Together with mechanistic and animal studies, this will allow us to better understand the systemic effect of formaldehyde exposure. PMID:21787879

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.

Identification of Effects of Regulatory Actions on Air Quality in Goods Movement Corridors in California.

PubMed

Su, Jason G; Meng, Ying-Ying; Pickett, Melissa; Seto, Edmund; Ritz, Beate; Jerrett, Michael

2016-08-16

Few studies have assessed the impact of regulatory actions on air quality improvement through a comprehensive monitoring effort. In this study, we designed saturation sampling of nitrogen oxides (NOX) for the counties of Los Angeles and Alameda (San Francisco Bay) before (2003-2007) and after (2008-2013) implementation of goods movement actions in California. We further separated the research regions into three location categories, including goods movement corridors (GMCs), nongoods movement corridors (NGMCs), and control areas (CTRLs). Linear mixed models were developed to identify whether reductions in NOX were greater in GMCs than in other areas, after controlling for potential confounding, including weather conditions (e.g., wind speed and temperature) and season of sampling. We also considered factors that might confound the relationship, including traffic and cargo volumes that may have changed due to economic downturn impacts. Compared to the pre-policy period, we found reductions of average pollutant concentrations for nitrogen dioxide (NO2) and NOX in GMCs of 6.4 and 21.7 ppb. The reductions were smaller in NGMCs (5.9 and 16.3 ppb, respectively) and in CTRLs (4.6 and 12.1 ppb, respectively). After controlling for potential confounding from weather conditions, season of sampling, and the economic downturn in 2008, the linear mixed models demonstrated that reductions in NO2 and NOX were significantly greater in GMCs compared to reductions observed in CTRLs; there were no statistically significant differences between NGMCs and CTRLs. These results indicate that policies regulating goods movement are achieving the desired outcome of improving air quality for the state, particularly in goods movement corridors where most disadvantaged communities live.

Driver Mortality in Paired Side Impact Collisions Due to Incompatible Vehicle Types

PubMed Central

Crandall, C.S.

2003-01-01

Using a matched case control design, this study measured the mortality associated with paired passenger car-sport utility vehicle side impact (‘T-bone’) collisions using FARS data. Survival versus fatal outcome within the matched crash pairs was measured with matched pair odds ratios. Conditional logistic regression adjusted for multiple effects. Overall, passenger car drivers experienced greater mortality than did SUV drivers, regardless if they were in the struck or striking vehicle (odds ratio: 10.0; 95% confidence interval: 7.9, 12.5). Differential mortality persisted after adjustment for confounders. Efforts should be sought to improve passenger car side impact crashworthiness and to reduce SUV aggressivity. PMID:12941243

One-Reason Decision Making Unveiled: A Measurement Model of the Recognition Heuristic

ERIC Educational Resources Information Center

Hilbig, Benjamin E.; Erdfelder, Edgar; Pohl, Rudiger F.

2010-01-01

The fast-and-frugal recognition heuristic (RH) theory provides a precise process description of comparative judgments. It claims that, in suitable domains, judgments between pairs of objects are based on recognition alone, whereas further knowledge is ignored. However, due to the confound between recognition and further knowledge, previous…

Unique Nanoparticle Properties Confound Fluorescent Based Assays Widely Employed in Their In Vitro Toxicity Testing and Ranking

EPA Science Inventory

Nanomaterials are a diverse collection of novel materials that exhibit at least one dimension less than 100 nm and display unique chemical and physical properties due to their nanoscale size. An emphasis has been put on developing high throughput screening (HTS) assays to charac...

Land surface controls on afternoon precipitation diagnosed from observational data: Uncertainties and confounding factors

USDA-ARS?s Scientific Manuscript database

The feedback between soil moisture and precipitation has long been a topic of interest due to its potential for improving weather and seasonal forecasts. The generally proposed mechanism assumes a control of soil moisture on precipitation via the partitioning of the surface fluxes (the Evaporative F...

Wheat curl mite and dry bulb mite: untangling a taxonomic conundrum through a multidisciplinary approach

USDA-ARS?s Scientific Manuscript database

The taxonomy of two economically important eriophyoid species, Aceria tosichella (wheat curl mite, WCM) and A. tulipae (dry bulb mite, DBM), was confounded in the world literature until the late 20th century due to their morphological similarity and ambiguous data from plant-transfer and virus-trans...

Unique Nanoparticle Optical Properties Confound Fluorescent Based Assays Widely Employed in Their In Vitro Toxicity Screening and Ranking

EPA Science Inventory

Nanoparticles (NPs) are novel materials having at least one dimension less than 100 nm and display unique physicochemical properties due to their nanoscale size. An emphasis has been placed on developing high throughput screening (HTS) assays to characterize and rank the toxiciti...

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

Influences of low-frequency and other noises produced by wind turbines: An epidemiological literature review.

PubMed

Kubo, Tatsuhiko; Hasunuma, Hideki; Morimatsu, Yoshitaka; Fujino, Yoshihisa; Hara, Kunio; Ishitake, Tatsuya

2017-01-01

Objectives　Due to its' environment-friendly and clean energy characteristics, wind power has been increasingly used globally, particularly in advanced countries. However, concerns about health hazards, especially due to low-frequency and other noises generated from wind turbines, have been reported repeatedly. In order to manage adverse health effects appropriately, regulatory standards or guidelines that consider the health of residents need to be developed. To provide a scientific basis for the development of such regulatory standards and guidelines, this paper conducted a literature review to analyze epidemiological studies involving residents living in the vicinity of wind farms.Methods　Using the PubMED database, epidemiological papers that examined the health effects of noises produced by wind turbines were searched and collected. Additional papers were collected from the abstracts presented at relevant international academic conferences such as the Inter-Noise 2013 and Wind Turbine Noise 2015. An evidence table comprising the study design, subjects, exposure assessment, outcomes, confounders, and research results of each selected study was created.Results　A total of 11 papers were collected (2 of which were abstracts from the international academic conferences). These studies reported outcomes such as perception of noises, annoyance caused by the noises, and the association of the noises with stress and sleeplessness. Significant associations between the noises or annoyance produced by wind turbines and subjective adverse health effects were reported repeatedly. Two studies reported an odds ratio of 1.1 for an increase of 1 dB in the A-weighted sound pressure level as a factor representing the influence level. For other factors, it was not possible to compare the magnitude of the impact among the collected studies. Individual attitudes toward wind power and landscapes, economic benefits of wind farms, visibility of wind turbines, sensitivity to sounds, and concerns over health hazards were reported as confounders.Conclusion　Significant associations between the noises or annoyance produced by wind turbines and subjective adverse health effects were reported repeatedly. However, there was insufficient evidence to conclude whether the annoyance was caused by the psychological response to the construction of wind farms or by the actual exposure to noises generated by wind farms.

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

Lifetime Alcohol Use & Cognitive Performance in Older Adults

PubMed Central

Kalapatapu, Raj K.; Ventura, Maria I.; Barnes, Deborah E.

2016-01-01

Background Substance use is an important clinical issue in the older adult population. As older adults are susceptible to cognitive disorders, the intersection of the fields of substance use and cognitive neuroscience is an active area of research. Prior studies of alcohol use and cognitive performance are mixed, and inconsistencies may be due to under- or over-adjustment for confounders. Aim This manuscript adds to this literature by conducting a secondary analysis of self-reported lifetime history of alcohol use and cognitive performance in older adults (n = 133). We hypothesized that current alcohol users would have poorer cognitive performance compared to never/minimal and former alcohol users. Methods Older adult participants were classified into never/minimal alcohol users, former alcohol users, and current alcohol users. A neurocognitive battery included a global cognitive measure and individual measures of attention, memory, fluency, and executive function. A directed acyclic graph (DAG)-based approach was used to select variables to be included in the multiple linear regression models. Results Though unadjusted analyses showed some significant associations between alcohol use and cognitive performance, all associations between alcohol use and cognitive performance were eliminated after adjusting for age, education, sex, race and smoking pack years. Alcohol drink years were not significantly associated with cognitive performance among current and former alcohol users. Discussion These results suggest that lifetime alcohol use is not significantly associated with cognitive performance in older adults after adjustment for key confounders. Inconsistencies in prior studies may be due to uncontrolled confounding and/or unnecessary adjustment of mediators and/or colliders. PMID:27719514

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

Association between wrist ratio and carpal tunnel syndrome: Effect modification by body mass index.

PubMed

Thiese, Matthew S; Merryweather, Andrew; Koric, Alzina; Ott, Ulrike; Wood, Eric M; Kapellusch, Jay; Foster, James; Garg, Arun; Deckow-Schaefer, Gwen; Tomich, Suzanna; Kendall, Richard; Drury, David L; Wertsch, Jacqueline; Hegmann, Kurt T

2017-12-01

Previous studies have reported higher wrist ratios (WR) related to carpal tunnel syndrome (CTS) but have not assessed effect modification by obesity and may have inadequately controlled for confounders. Baseline data of a multicenter prospective cohort study were analyzed. CTS was defined by nerve conduction study (NCS) criteria and symptoms. Among the 1,206 participants, a square-shaped wrist was associated with CTS after controlling for confounders (prevalence ratio = 2.27; 95% confidence interval [95% CI], 1.33-3.86). Body mass index (BMI) was a strong effect modifier on the relationship between WR and both CTS and abnormal NCS results, with normal weight strata of rectangular versus square wrists = 8.18 (95% CI, 1.63-49.96) and 7.12 (95% CI, 2.19-23.16), respectively. A square wrist is significantly associated with CTS after controlling for confounders. Effect modification by high BMI masked the eightfold magnitude adjusted relationship seen between WR and CTS among normal weight participants. Muscle Nerve 56: 1047-1053, 2017. © 2017 Wiley Periodicals, Inc.

To be or not to be associated: power study of four statistical modeling approaches to identify parasite associations in cross-sectional studies

PubMed Central

Vaumourin, Elise; Vourc'h, Gwenaël; Telfer, Sandra; Lambin, Xavier; Salih, Diaeldin; Seitzer, Ulrike; Morand, Serge; Charbonnel, Nathalie; Vayssier-Taussat, Muriel; Gasqui, Patrick

2014-01-01

A growing number of studies are reporting simultaneous infections by parasites in many different hosts. The detection of whether these parasites are significantly associated is important in medicine and epidemiology. Numerous approaches to detect associations are available, but only a few provide statistical tests. Furthermore, they generally test for an overall detection of association and do not identify which parasite is associated with which other one. Here, we developed a new approach, the association screening approach, to detect the overall and the detail of multi-parasite associations. We studied the power of this new approach and of three other known ones (i.e., the generalized chi-square, the network and the multinomial GLM approaches) to identify parasite associations either due to parasite interactions or to confounding factors. We applied these four approaches to detect associations within two populations of multi-infected hosts: (1) rodents infected with Bartonella sp., Babesia microti and Anaplasma phagocytophilum and (2) bovine population infected with Theileria sp. and Babesia sp. We found that the best power is obtained with the screening model and the generalized chi-square test. The differentiation between associations, which are due to confounding factors and parasite interactions was not possible. The screening approach significantly identified associations between Bartonella doshiae and B. microti, and between T. parva, T. mutans, and T. velifera. Thus, the screening approach was relevant to test the overall presence of parasite associations and identify the parasite combinations that are significantly over- or under-represented. Unraveling whether the associations are due to real biological interactions or confounding factors should be further investigated. Nevertheless, in the age of genomics and the advent of new technologies, it is a considerable asset to speed up researches focusing on the mechanisms driving interactions between parasites. PMID:24860791

[Association between ambient PM(l0)/PM(2.5) concentration and outpatient department visits due to respiratory disease in a hospital in Jinan, 2013-2015: a time series analysis].

PubMed

Zhao, M J; Geng, X Y; Cui, L L; Zhou, J W; Zhang, J

2017-03-10

Objective: To estimate the influence of the ambient PM(l0) and PM(2.5) pollution on the hospital outpatient department visit due to respiratory diseases in local residents in Jinan quantitatively. Methods: Time serial analysis using generalized addictive model (GAM) was conducted. After controlling the confounding factors, such as long term trend, weekly pattern and meteorological factors, considering lag effect and the influence of other air pollutants, the excess relative risks of daily hospital visits associated with increased ambient PM(10) and PM(2.5) levels were estimated by fitting a Poisson regression model. Results: A 10 μg/m(3) increase of PM(10) and PM(2.5) levels was associated with an increase of 0.36%(95 %CI : 0.30%-0.43%) and 0.50%(95 %CI : 0.30%-0.70%) respectively for hospital visits due to respiratory diseases. Lag effect of 6 days was strongest, the excess relative risks were 0.65% (95 % CI : 0.58% -0.71% ) and 0.54% (95 % CI : 0.42%-0.67%) respectively. When NO(2) concentration was introduced, the daily hospital visits due to respiratory disease increased by 0.83% as a 10 μg/m(3) increase of PM(10) concentration (95 % CI : 0.76%-0.91%). Conclusion: The ambient PM(l0) and PM(2.5) pollution was positively associated with daily hospital visits due to respiratory disease in Jinan, and ambient NO(2) concentration would have the synergistic effect.

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.

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).

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.

Human exposure to high natural background radiation: what can it teach us about radiation risks?

PubMed Central

Hendry, Jolyon H; Simon, Steven L; Wojcik, Andrzej; Sohrabi, Mehdi; Burkart, Werner; Cardis, Elisabeth; Laurier, Dominique; Tirmarche, Margot; Hayata, Isamu

2014-01-01

Natural radiation is the major source of human exposure to ionising radiation, and its largest contributing component to effective dose arises from inhalation of 222Rn and its radioactive progeny. However, despite extensive knowledge of radiation risks gained through epidemiologic investigations and mechanistic considerations, the health effects of chronic low-level radiation exposure are still poorly understood. The present paper reviews the possible contribution of studies of populations living in high natural background radiation (HNBR) areas (Guarapari, Brazil; Kerala, India; Ramsar, Iran; Yangjiang, China), including radon-prone areas, to low dose risk estimation. Much of the direct information about risk related to HNBR comes from case–control studies of radon and lung cancer, which provide convincing evidence of an association between long-term protracted radiation exposures in the general population and disease incidence. The success of these studies is mainly due to the careful organ dose reconstruction (with relatively high doses to the lung), and to the fact that large-scale collaborative studies have been conducted to maximise the statistical power and to ensure the systematic collection of information on potential confounding factors. In contrast, studies in other (non-radon) HNBR areas have provided little information, relying mainly on ecological designs and very rough effective dose categorisations. Recent steps taken in China and India to establish cohorts for follow-up and to conduct nested case–control studies may provide useful information about risks in the future, provided that careful organ dose reconstruction is possible and information is collected on potential confounding factors. PMID:19454802

Testing the dose-response specification in epidemiology: public health and policy consequences for lead.

PubMed

Rothenberg, Stephen J; Rothenberg, Jesse C

2005-09-01

Statistical evaluation of the dose-response function in lead epidemiology is rarely attempted. Economic evaluation of health benefits of lead reduction usually assumes a linear dose-response function, regardless of the outcome measure used. We reanalyzed a previously published study, an international pooled data set combining data from seven prospective lead studies examining contemporaneous blood lead effect on IQ (intelligence quotient) of 7-year-old children (n = 1,333). We constructed alternative linear multiple regression models with linear blood lead terms (linear-linear dose response) and natural-log-transformed blood lead terms (log-linear dose response). We tested the two lead specifications for nonlinearity in the models, compared the two lead specifications for significantly better fit to the data, and examined the effects of possible residual confounding on the functional form of the dose-response relationship. We found that a log-linear lead-IQ relationship was a significantly better fit than was a linear-linear relationship for IQ (p = 0.009), with little evidence of residual confounding of included model variables. We substituted the log-linear lead-IQ effect in a previously published health benefits model and found that the economic savings due to U.S. population lead decrease between 1976 and 1999 (from 17.1 microg/dL to 2.0 microg/dL) was 2.2 times (319 billion dollars) that calculated using a linear-linear dose-response function (149 billion dollars). The Centers for Disease Control and Prevention action limit of 10 microg/dL for children fails to protect against most damage and economic cost attributable to lead exposure.

Empirical evaluation of data normalization methods for molecular classification.

PubMed

Huang, Huei-Chung; Qin, Li-Xuan

2018-01-01

Data artifacts due to variations in experimental handling are ubiquitous in microarray studies, and they can lead to biased and irreproducible findings. A popular approach to correct for such artifacts is through post hoc data adjustment such as data normalization. Statistical methods for data normalization have been developed and evaluated primarily for the discovery of individual molecular biomarkers. Their performance has rarely been studied for the development of multi-marker molecular classifiers-an increasingly important application of microarrays in the era of personalized medicine. In this study, we set out to evaluate the performance of three commonly used methods for data normalization in the context of molecular classification, using extensive simulations based on re-sampling from a unique pair of microRNA microarray datasets for the same set of samples. The data and code for our simulations are freely available as R packages at GitHub. In the presence of confounding handling effects, all three normalization methods tended to improve the accuracy of the classifier when evaluated in an independent test data. The level of improvement and the relative performance among the normalization methods depended on the relative level of molecular signal, the distributional pattern of handling effects (e.g., location shift vs scale change), and the statistical method used for building the classifier. In addition, cross-validation was associated with biased estimation of classification accuracy in the over-optimistic direction for all three normalization methods. Normalization may improve the accuracy of molecular classification for data with confounding handling effects; however, it cannot circumvent the over-optimistic findings associated with cross-validation for assessing classification accuracy.

I can see what you are saying: Auditory labels reduce visual search times.

PubMed

Cho, Kit W

2016-10-01

The present study explored the self-directed-speech effect, the finding that relative to silent reading of a label (e.g., DOG), saying it aloud reduces visual search reaction times (RTs) for locating a target picture among distractors. Experiment 1 examined whether this effect is due to a confound in the differences in the number of cues in self-directed speech (two) vs. silent reading (one) and tested whether self-articulation is required for the effect. The results showed that self-articulation is not required and that merely hearing the auditory label reduces visual search RTs relative to silent reading. This finding also rules out the number of cues confound. Experiment 2 examined whether hearing an auditory label activates more prototypical features of the label's referent and whether the auditory-label benefit is moderated by the target's imagery concordance (the degree to which the target picture matches the mental picture that is activated by a written label for the target). When the target imagery concordance was high, RTs following the presentation of a high prototypicality picture or auditory cue were comparable and shorter than RTs following a visual label or low prototypicality picture cue. However, when the target imagery concordance was low, RTs following an auditory cue were shorter than the comparable RTs following the picture cues and visual-label cue. The results suggest that an auditory label activates both prototypical and atypical features of a concept and can facilitate visual search RTs even when compared to picture primes. Copyright © 2016 Elsevier B.V. All rights reserved.

Pulmonary function and fuel use: A population survey

PubMed Central

Saha, Asim; Mohan Rao, N; Kulkarni, PK; Majumdar, PK; Saiyed, HN

2005-01-01

Background In the backdrop of conflicting reports (some studies reported adverse outcomes of biomass fuel use whereas few studies reported absence of any association between adverse health effect and fuel use, may be due to presence of large number of confounding variables) on the respiratory health effects of biomass fuel use, this cross sectional survey was undertaken to understand the role of fuel use on pulmonary function. Method This study was conducted in a village of western India involving 369 randomly selected adult subjects (165 male and 204 female). All the subjects were interviewed and were subjected to pulmonary function test. Analysis of covariance was performed to compare the levels of different pulmonary function test parameters in relation to different fuel use taking care of the role of possible confounding factors. Results This study showed that biomass fuel use (especially wood) is an important factor for deterioration of pulmonary function (particularly in female). FEV1 (p < .05), FEV1 % (p < .01), PEFR (p < .05) and FEF25–75 (p < .01) values were significantly lower in biomass fuel using females than nonusers. Comparison of only biomass fuel use vs. only LPG (Liquefied Petroleum Gas) use and only wood vs. only LPG use has showed that LPG is a safer fuel so far as deterioration of pulmonary function is concerned. This study observes some deterioration of pulmonary function in the male subjects also, who came from biomass fuel using families. Conclusion This study concluded that traditional biomass fuels like wood have adverse effects on pulmonary function. PMID:16255784

A Genetically Informed Study of the Processes Underlying the Association Between Parental Marital Instability and Offspring Adjustment

PubMed Central

D’Onofrio, Brian M.; Turkheimer, Eric; Emery, Robert E.; Heath, Andrew C.; Madden, Pamela A.; Slutske, Wendy S.; Martin, Nicholas G.

2010-01-01

Parental divorce is associated with problematic offspring adjustment, but the relation may be due to shared genetic or environmental factors. One way to test for these confounds is to study offspring of twins discordant for divorce. The current analyses used this design to separate the mechanisms responsible for the association between parental divorce, experienced either before or after the age of 16, and offspring well-being. The results were consistent with a causal role of divorce in earlier initiation of sexual intercourse and emotional difficulties, in addition to a greater probability of educational problems, depressed mood, and suicidal ideation. In contrast, the increased risk for cohabitation and earlier initiation of drug use was explained by selection factors, including genetic confounds. PMID:16756440

Effects of white matter microstructure on phase and susceptibility maps.

PubMed

Wharton, Samuel; Bowtell, Richard

2015-03-01

To investigate the effects on quantitative susceptibility mapping (QSM) and susceptibility tensor imaging (STI) of the frequency variation produced by the microstructure of white matter (WM). The frequency offsets in a WM tissue sample that are not explained by the effect of bulk isotropic or anisotropic magnetic susceptibility, but rather result from the local microstructure, were characterized for the first time. QSM and STI were then applied to simulated frequency maps that were calculated using a digitized whole-brain, WM model formed from anatomical and diffusion tensor imaging data acquired from a volunteer. In this model, the magnitudes of the frequency contributions due to anisotropy and microstructure were derived from the results of the tissue experiments. The simulations suggest that the frequency contribution of microstructure is much larger than that due to bulk effects of anisotropic magnetic susceptibility. In QSM, the microstructure contribution introduced artificial WM heterogeneity. For the STI processing, the microstructure contribution caused the susceptibility anisotropy to be significantly overestimated. Microstructure-related phase offsets in WM yield artifacts in the calculated susceptibility maps. If susceptibility mapping is to become a robust MRI technique, further research should be carried out to reduce the confounding effects of microstructure-related frequency contributions. © 2014 Wiley Periodicals, Inc.

Effects of White Matter Microstructure on Phase and Susceptibility Maps

PubMed Central

Wharton, Samuel; Bowtell, Richard

2015-01-01

Purpose To investigate the effects on quantitative susceptibility mapping (QSM) and susceptibility tensor imaging (STI) of the frequency variation produced by the microstructure of white matter (WM). Methods The frequency offsets in a WM tissue sample that are not explained by the effect of bulk isotropic or anisotropic magnetic susceptibility, but rather result from the local microstructure, were characterized for the first time. QSM and STI were then applied to simulated frequency maps that were calculated using a digitized whole-brain, WM model formed from anatomical and diffusion tensor imaging data acquired from a volunteer. In this model, the magnitudes of the frequency contributions due to anisotropy and microstructure were derived from the results of the tissue experiments. Results The simulations suggest that the frequency contribution of microstructure is much larger than that due to bulk effects of anisotropic magnetic susceptibility. In QSM, the microstructure contribution introduced artificial WM heterogeneity. For the STI processing, the microstructure contribution caused the susceptibility anisotropy to be significantly overestimated. Conclusion Microstructure-related phase offsets in WM yield artifacts in the calculated susceptibility maps. If susceptibility mapping is to become a robust MRI technique, further research should be carried out to reduce the confounding effects of microstructure-related frequency contributions. Magn Reson Med 73:1258–1269, 2015. © 2014 Wiley Periodicals, Inc. PMID:24619643

An investigation into the relationship between age and physiological function in highly active older adults

PubMed Central

Pollock, Ross D; Carter, Scott; Velloso, Cristiana P; Duggal, Niharika A; Lord, Janet M; Lazarus, Norman R; Harridge, Stephen D R

2015-01-01

Despite extensive research, the relationship between age and physiological function remains poorly characterised and there are currently no reliable markers of human ageing. This is probably due to a number of confounding factors, particularly in studies of a cross-sectional nature. These include inter-subject genetic variation, as well as inter-generational differences in nutrition, healthcare and insufficient levels of physical activity as well as other environmental factors. We have studied a cohort of highly and homogeneously active older male (n = 84) and female (n = 41) cyclists aged 55–79 years who it is proposed represent a model for the study of human ageing free from the majority of confounding factors, especially inactivity. The aim of the study was to identify physiological markers of ageing by assessing the relationship between function and age across a wide range of indices. Each participant underwent a detailed physiological profiling which included measures of cardiovascular, respiratory, neuromuscular, metabolic, endocrine and cognitive functions, bone strength, and health and well-being. Significant associations between age and function were observed for many functions. The maximal rate of oxygen consumption ( showed the closest association with age (r = −0.443 to −0.664; P < 0.001), but even here the variance in age for any given level was high, precluding the clear identification of the age of any individual. The results of this cross-sectional study suggest that even when many confounding variables are removed the relationship between function and healthy ageing is complex and likely to be highly individualistic and that physical activity levels must be taken into account in ageing studies. Key Points The relationship between age and physiological function remains poorly defined and there are no physiological markers that can be used to reliably predict the age of an individual. This could be due to a variety of confounding genetic and lifestyle factors, and in particular to ill-defined and low levels of physical activity. This study assessed the relationship between age and a diverse range of physiological functions in a cohort of highly active older individuals (cyclists) aged 55–79 years in whom the effects of lifestyle factors would be ameliorated. Significant associations between age and function were observed for many functions. was most closely associated with age, but even here the variance in age for any given level was high, precluding the clear identification of the age of any individual. The data suggest that the relationship between human ageing and physiological function is highly individualistic and modified by inactivity. PMID:25565071

An investigation into the relationship between age and physiological function in highly active older adults.

PubMed

Pollock, Ross D; Carter, Scott; Velloso, Cristiana P; Duggal, Niharika A; Lord, Janet M; Lazarus, Norman R; Harridge, Stephen D R

2015-02-01

The relationship between age and physiological function remains poorly defined and there are no physiological markers that can be used to reliably predict the age of an individual. This could be due to a variety of confounding genetic and lifestyle factors, and in particular to ill-defined and low levels of physical activity. This study assessed the relationship between age and a diverse range of physiological functions in a cohort of highly active older individuals (cyclists) aged 55-79 years in whom the effects of lifestyle factors would be ameliorated. Significant associations between age and function were observed for many functions. V̇O2max was most closely associated with age, but even here the variance in age for any given level was high, precluding the clear identification of the age of any individual. The data suggest that the relationship between human ageing and physiological function is highly individualistic and modified by inactivity. Despite extensive research, the relationship between age and physiological function remains poorly characterised and there are currently no reliable markers of human ageing. This is probably due to a number of confounding factors, particularly in studies of a cross-sectional nature. These include inter-subject genetic variation, as well as inter-generational differences in nutrition, healthcare and insufficient levels of physical activity as well as other environmental factors. We have studied a cohort of highly and homogeneously active older male (n = 84) and female (n = 41) cyclists aged 55-79 years who it is proposed represent a model for the study of human ageing free from the majority of confounding factors, especially inactivity. The aim of the study was to identify physiological markers of ageing by assessing the relationship between function and age across a wide range of indices. Each participant underwent a detailed physiological profiling which included measures of cardiovascular, respiratory, neuromuscular, metabolic, endocrine and cognitive functions, bone strength, and health and well-being. Significant associations between age and function were observed for many functions. The maximal rate of oxygen consumption (V̇O2max) showed the closest association with age (r = -0.443 to -0.664; P < 0.001), but even here the variance in age for any given level was high, precluding the clear identification of the age of any individual. The results of this cross-sectional study suggest that even when many confounding variables are removed the relationship between function and healthy ageing is complex and likely to be highly individualistic and that physical activity levels must be taken into account in ageing studies. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.

Causal diagrams and multivariate analysis III: confound it!

PubMed

Jupiter, Daniel C

2015-01-01

This commentary concludes my series concerning inclusion of variables in multivariate analyses. We take up the issues of confounding and effect modification and summarize the work we have thus far done. Finally, we provide a rough algorithm to help guide us through the maze of possibilities that we have outlined. Copyright © 2015 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. 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.

Does Metformin Reduce Cancer Risks? Methodologic Considerations.

PubMed

Golozar, Asieh; Liu, Shuiqing; Lin, Joeseph A; Peairs, Kimberly; Yeh, Hsin-Chieh

2016-01-01

The substantial burden of cancer and diabetes and the association between the two conditions has been a motivation for researchers to look for targeted strategies that can simultaneously affect both diseases and reduce their overlapping burden. In the absence of randomized clinical trials, researchers have taken advantage of the availability and richness of administrative databases and electronic medical records to investigate the effects of drugs on cancer risk among diabetic individuals. The majority of these studies suggest that metformin could potentially reduce cancer risk. However, the validity of this purported reduction in cancer risk is limited by several methodological flaws either in the study design or in the analysis. Whether metformin use decreases cancer risk relies heavily on the availability of valid data sources with complete information on confounders, accurate assessment of drug use, appropriate study design, and robust analytical techniques. The majority of the observational studies assessing the association between metformin and cancer risk suffer from methodological shortcomings and efforts to address these issues have been incomplete. Future investigations on the association between metformin and cancer risk should clearly address the methodological issues due to confounding by indication, prevalent user bias, and time-related biases. Although the proposed strategies do not guarantee a bias-free estimate for the association between metformin and cancer, they will reduce synthesis of and reporting of erroneous results.

Is Self-Regulation "All in the family"? Testing Environmental Effects using Within-Family Quasi-Experiments.

PubMed

Deater-Deckard, Kirby

2016-05-01

Most of the individual difference variance in the population is found within families, yet studying the processes causing this variation is difficult due to confounds between genetic and nongenetic influences. Quasi-experiments can be used to test hypotheses regarding environment exposure (e.g., timing, duration) while controlling for genetic confounds. To illustrate, two studies of cognitive self-regulation in childhood (i.e., working memory [WM], effortful control [EC], attention span/persistence [A/P]) are presented. Study 1 utilized an identical twin differences design ( N = 85 to 98 pairs) to control for genetic differences while using relative twin birth weight difference to predict relative twin difference in WM and EC. Larger relative twin difference in WM and EF was predicted by the combination of shorter gestation and larger relative birth weight difference. Study 2 utilized an adoptive sibling relative difference design ( N = 123 same-sex pairs) to control for genetic similarity while using relative sibling difference in the age at time of adoption to predict relative sibling difference in A/P. Larger relative sibling difference in A/P was predicted by the combination of larger relative difference in time in the adoptive home and age at adoption. Within-family quasi-experimental designs allow stronger inferences about hypothesized environmental influences than between-family designs permit.

Effectiveness in prevention of travellers' diarrhoea by an oral cholera vaccine WC/rBS.

PubMed

López-Gigosos, R; García-Fortea, P; Reina-Doña, E; Plaza-Martín, E

2007-11-01

To investigate the effectiveness of an oral cholera vaccine (Dukoral((R))) in preventing travellers' diarrhoea. A retrospective study was conducted among travellers who had attended the International Vaccination Centre in Malaga, Spain, before starting their journey. A telephone interview was undertaken from November 2005 to January 2006 after the travellers had returned from their trip. The relationship between vaccination with Dukoral((R)) and travellers' diarrhoea was analysed by means of a logistic regression model, adjusting for possible confounding variables (traveller's age, duration of trip and region visited). The overall incidence of diarrhoea in vaccinated travellers was 23% compared with 40% in non-vaccinated travellers (historical control group) (p=0.004). Short episodes of diarrhoea were reported in significantly more travellers of the vaccinated group than of the non-vaccinated group (average duration of diarrhoea 2.21 days versus 3.97 days, p=0.005). The incidence of diarrhoea was significantly lower among vaccinated than non-vaccinated travellers who went to Africa for less than 3 weeks (16% versus 48%, p=0.002) or India and South East Asia (19% versus 50%, p =0.052) for more than 3 weeks. No adverse events were reported in the group of vaccinated travellers. Vaccination reduced the risk of travellers' diarrhoea by 43%; possibly due to the protective effect of the oral vaccine Dukoral((R)) against travellers' diarrhoea caused by enterotoxigenic Escherichia coli (ETEC) or cholera. The efficacy of vaccination increased after adjusting for confounding factors, being modified by traveller age (under 30 years, or 45 years and older the protective effect of the vaccine is 4.8 greater, 95% confidence interval (CI): 2.1-10.7). The number needed to treat to prevent one traveller from suffering from one or more episodes of travellers' diarrhoea was 5.8.

Childhood adversity is linked to differential brain volumes in adolescents with alcohol use disorder: a voxel-based morphometry study.

PubMed

Brooks, Samantha J; Dalvie, Shareefa; Cuzen, Natalie L; Cardenas, Valerie; Fein, George; Stein, Dan J

2014-06-01

Previous neuroimaging studies link both alcohol use disorder (AUD) and early adversity to neurobiological differences in the adult brain. However, the association between AUD and childhood adversity and effects on the developing adolescent brain are less clear, due in part to the confound of psychiatric comorbidity. Here we examine early life adversity and its association with brain volume in a unique sample of 116 South African adolescents (aged 12-16) with AUD but without psychiatric comorbidity. Participants were 58 adolescents with DSM-IV alcohol dependence and with no other psychiatric comorbidities, and 58 age-, gender- and protocol-matched light/non-drinking controls (HC). Assessments included the Childhood Trauma Questionnaire (CTQ). MR images were acquired on a 3T Siemens Magnetom Allegra scanner. Volumes of global and regional structures were estimated using SPM8 Voxel Based Morphometry (VBM), with analysis of covariance (ANCOVA) and regression analyses. In whole brain ANCOVA analyses, a main effect of group when examining the AUD effect after covarying out CTQ was observed on brain volume in bilateral superior temporal gyrus. Subsequent regression analyses to examine how childhood trauma scores are linked to brain volumes in the total cohort revealed a negative correlation in the left hippocampus and right precentral gyrus. Furthermore, bilateral (but most significantly left) hippocampal volume was negatively associated with sub-scores on the CTQ in the total cohort. These findings support our view that some alterations found in brain volumes in studies of adolescent AUD may reflect the impact of confounding factors such as psychiatric comorbidity rather than the effects of alcohol per se. In particular, early life adversity may influence the developing adolescent brain in specific brain regions, such as the hippocampus.

Effects of gender and executive function on visuospatial working memory in adult obsessive-compulsive disorder.

PubMed

Martoni, Riccardo Maria; Salgari, Giulia; Galimberti, Elisa; Cavallini, Maria Cristina; O'Neill, Joseph

2015-12-01

Visuospatial working memory (VSWM) is the ability of the brain to transiently store and manipulate visual information. VSWM deficiencies have been reported in obsessive-compulsive disorder (OCD), but not consistently, perhaps due to variability in task design and clinical patient factors. To explore this variability, this study assessed effects of the design factors task difficulty and executive organizational strategy and of the clinical factors gender, OCD symptom dimension, and duration of illness on VSWM in OCD. The CANTAB spatial working memory, spatial recognition memory, delayed matching to sample, and stop signal tasks were administered to 42 adult OCD patients and 42 age- and sex-matched healthy controls. Aims were to detect a possible VSWM deficit in the OCD sample, to evaluate influences of the above task and patient factors, to determine the specificity of the deficit to the visuospatial subdomain, and to examine effects of sustained attention as potential neurocognitive confound. We confirmed previous findings of a VSWM deficit in OCD that was more severe for greater memory load (task difficulty) and that was affected by task strategy (executive function). We failed to demonstrate significant deficits in neighboring or confounding neurocognitive subdomains (visual object recognition or visual object short-term memory, sustained attention). Notably, the VSWM deficit was only significant for female patients, adding to evidence for sexual dimorphism in OCD. Again as in prior work, more severe OCD symptoms in the symmetry dimension (but no other dimension) significantly negatively impacted VSWM. Duration of illness had no significant effect on VSWM. VSWM deficits in OCD appear more severe with higher task load and may be mediated through poor task strategy. Such deficits may present mainly in female patients and in (male and female) patients with symmetry symptoms.

The Use of Propensity Scores and Observational Data to Estimate Randomized Controlled Trial Generalizability Bias

PubMed Central

Pressler, Taylor R.; Kaizar, Eloise E.

2014-01-01

While randomized controlled trials (RCT) are considered the “gold standard” for clinical studies, the use of exclusion criteria may impact the external validity of the results. It is unknown whether estimators of effect size are biased by excluding a portion of the target population from enrollment. We propose to use observational data to estimate the bias due to enrollment restrictions, which we term generalizability bias. In this paper we introduce a class of estimators for the generalizability bias and use simulation to study its properties in the presence of non-constant treatment effects. We find the surprising result that our estimators can be unbiased for the true generalizability bias even when all potentially confounding variables are not measured. In addition, our proposed doubly robust estimator performs well even for mis-specified models. PMID:23553373

Assessing the Accuracy of Generalized Inferences From Comparison Group Studies Using a Within-Study Comparison Approach: The Methodology.

PubMed

Jaciw, Andrew P

2016-06-01

Various studies have examined bias in impact estimates from comparison group studies (CGSs) of job training programs, and in education, where results are benchmarked against experimental results. Such within-study comparison (WSC) approaches investigate levels of bias in CGS-based impact estimates, as well as the success of various design and analytic strategies for reducing bias. This article reviews past literature and summarizes conditions under which CGSs replicate experimental benchmark results. It extends the framework to, and develops the methodology for, situations where results from CGSs are generalized to untreated inference populations. Past research is summarized; methods are developed to examine bias in program impact estimates based on cross-site comparisons in a multisite trial that are evaluated against site-specific experimental benchmarks. Students in Grades K-3 in 79 schools in Tennessee; students in Grades 4-8 in 82 schools in Alabama. Grades K-3 Stanford Achievement Test (SAT) in reading and math scores; Grades 4-8 SAT10 reading scores. Past studies show that bias in CGS-based estimates can be limited through strong design, with local matching, and appropriate analysis involving pretest covariates and variables that represent selection processes. Extension of the methodology to investigate accuracy of generalized estimates from CGSs shows bias from confounders and effect moderators. CGS results, when extrapolated to untreated inference populations, may be biased due to variation in outcomes and impact. Accounting for effects of confounders or moderators may reduce bias. © The Author(s) 2016.

High angular resolution diffusion imaging with stimulated echoes: compensation and correction in experiment design and analysis.

PubMed

Lundell, Henrik; Alexander, Daniel C; Dyrby, Tim B

2014-08-01

Stimulated echo acquisition mode (STEAM) diffusion MRI can be advantageous over pulsed-gradient spin-echo (PGSE) for diffusion times that are long compared with T2 . It therefore has potential for biomedical diffusion imaging applications at 7T and above where T2 is short. However, gradient pulses other than the diffusion gradients in the STEAM sequence contribute much greater diffusion weighting than in PGSE and lead to a disrupted experimental design. Here, we introduce a simple compensation to the STEAM acquisition that avoids the orientational bias and disrupted experiment design that these gradient pulses can otherwise produce. The compensation is simple to implement by adjusting the gradient vectors in the diffusion pulses of the STEAM sequence, so that the net effective gradient vector including contributions from diffusion and other gradient pulses is as the experiment intends. High angular resolution diffusion imaging (HARDI) data were acquired with and without the proposed compensation. The data were processed to derive standard diffusion tensor imaging (DTI) maps, which highlight the need for the compensation. Ignoring the other gradient pulses, a bias in DTI parameters from STEAM acquisition is found, due both to confounds in the analysis and the experiment design. Retrospectively correcting the analysis with a calculation of the full B matrix can partly correct for these confounds, but an acquisition that is compensated as proposed is needed to remove the effect entirely. © 2014 The Authors. NMR in Biomedicine published by John Wiley & Sons, Ltd.

Non-allergic cutaneous reactions in airborne chemical sensitivity--a population based study.

PubMed

Berg, Nikolaj Drimer; Linneberg, Allan; Thyssen, Jacob Pontoppidan; Dirksen, Asger; Elberling, Jesper

2011-06-01

Multiple chemical sensitivity (MCS) is characterised by adverse effects due to exposure to low levels of chemical substances. The aetiology is unknown, but chemical related respiratory symptoms have been found associated with positive patch test. The purpose of this study was to investigate the relationship between cutaneous reactions from patch testing and self-reported severity of chemical sensitivity to common airborne chemicals. A total of 3460 individuals participating in a general health examination, Health 2006, were patch tested with allergens from the European standard series and screened for chemical sensitivity with a standardised questionnaire dividing the participants into four severity groups of chemical sensitivity. Both allergic and non-allergic cutaneous reactions--defined as irritative, follicular, or doubtful allergic reactions--were analysed in relationship with severity of chemical sensitivity. Associations were controlled for the possible confounding effects of sex, age, asthma, eczema, atopic dermatitis, psychological and social factors, and smoking habits. In unadjusted analyses we found associations between allergic and non-allergic cutaneous reactions on patch testing and the two most severe groups of self-reported sensitivity to airborne chemicals. When adjusting for confounding, associations were weakened, and only non-allergic cutaneous reactions were significantly associated with individuals most severely affected by inhalation of airborne chemicals (odds ratio = 2.5, p = 0.006). Our results suggest that individuals with self-reported chemical sensitivity show increased non-allergic cutaneous reactions based on day 2 readings of patch tests. Copyright © 2011 Elsevier GmbH. All rights reserved.

Impact of (+/-)-catechin on soil microbial communities.

PubMed

Inderjit; Kaur, Rajwant; Kaur, Surinder; Callaway, Ragan M

2009-01-01

Catechin is a highly studied but controversial allelochemical reported as a component of the root exudates of Centaurea maculosa. Initial reports of high and consistent exudation rates and soil concentrations have been shown to be highly inaccurate, but the chemical has been found in root exudates at and much less frequently in soil but sporadically at high concentrations. Part of the problem of detection and measuring phytotoxicity in natural soils may be due to the confounding effect of soil microbes, and little is known about interactions between catechin and soil microbes. Here we tested the effect of catechin on soil microbial communities and the feedback of these effects to two plant species. We found that catechin inhibits microbial activity in the soil we tested, and by doing so appears to promote plant growth in the microbe-free environment. This is in striking contrast to other in vitro studies, emphasizing the highly conditional effects of the chemical and suggesting that the phytotoxic effects of catechin may be exerted through the microbes in some soils.

School Violent Crime and Academic Achievement in Chicago*

PubMed Central

Burdick-Will, Julia

2013-01-01

Educational outcomes vary dramatically across schools in the United States. Many under-performing schools, especially in Chicago, also deal with high levels of violent crime on school grounds. Exposure to this type of frequent violence may be an important factor shaping already disadvantaged students’ educational experiences. However, estimating the effect of school violence on learning is difficult due to potential selection bias and the confounding of other school-level problems. Using detailed crime data from the Chicago Police Department, complete administrative records from the Chicago Public Schools, and school climate surveys conducted by the Consortium on Chicago School Research (2002–10), this study exploits variation in violent crime rates within schools over time to estimate its effect on academic achievement. School and neighborhood fixed-effects models show that violent crime rates have a negative effect on test scores, but not on grades. This effect is more likely related to direct reductions in learning, through cognitive stress and classroom disruptions, than changes in perceived safety, general school climate, or discipline practices. PMID:24259755

Impact of (±)-catechin on soil microbial communities

PubMed Central

Kaur, Rajwant; Kaur, Surinder

2009-01-01

Catechin is a highly studied but controversial allelochemical reported as a component of the root exudates of Centaurea maculosa. Initial reports of high and consistent exudation rates and soil concentrations have been shown to be highly inaccurate, but the chemical has been found in root exudates at and much less frequently in soil but sporadically at high concentrations. Part of the problem of detection and measuring phytotoxicity in natural soils may be due to the confounding effect of soil microbes, and little is known about interactions between catechin and soil microbes. Here we tested the effect of catechin on soil microbial communities and the feedback of these effects to two plant species. We found that catechin inhibits microbial activity in the soil we tested, and by doing so appears to promote plant growth in the microbe-free environment. This is in striking contrast to other in vitro studies, emphasizing the highly conditional effects of the chemical and suggesting that the phytotoxic effects of catechin may be exerted through the microbes in some soils. PMID:19704908

School Violent Crime and Academic Achievement in Chicago.

PubMed

Burdick-Will, Julia

2013-10-01

Educational outcomes vary dramatically across schools in the United States. Many under-performing schools, especially in Chicago, also deal with high levels of violent crime on school grounds. Exposure to this type of frequent violence may be an important factor shaping already disadvantaged students' educational experiences. However, estimating the effect of school violence on learning is difficult due to potential selection bias and the confounding of other school-level problems. Using detailed crime data from the Chicago Police Department, complete administrative records from the Chicago Public Schools, and school climate surveys conducted by the Consortium on Chicago School Research (2002-10), this study exploits variation in violent crime rates within schools over time to estimate its effect on academic achievement. School and neighborhood fixed-effects models show that violent crime rates have a negative effect on test scores, but not on grades. This effect is more likely related to direct reductions in learning, through cognitive stress and classroom disruptions, than changes in perceived safety, general school climate, or discipline practices.

Offspring ADHD as a risk factor for parental marital problems: controls for genetic and environmental confounds.

PubMed

Schermerhorn, Alice C; D'Onofrio, Brian M; Slutske, Wendy S; Emery, Robert E; Turkheimer, Eric; Harden, K Paige; Heath, Andrew C; Martin, Nicholas G

2012-12-01

Previous studies have found that child attention-deficit/hyperactivity disorder (ADHD) is associated with more parental marital problems. However, the reasons for this association are unclear. The association might be due to genetic or environmental confounds that contribute to both marital problems and ADHD. Data were drawn from the Australian Twin Registry, including 1,296 individual twins, their spouses, and offspring. We studied adult twins who were discordant for offspring ADHD.Using a discordant twin pairs design, we examined the extent to which genetic and environmental confounds,as well as measured parental and offspring characteristics, explain the ADHD-marital problems association. Offspring ADHD predicted parental divorce and marital conflict. The associations were also robust when comparing differentially exposed identical twins to control for unmeasured genetic and environmental factors, when controlling for measured maternal and paternal psychopathology,when restricting the sample based on timing of parental divorce and ADHD onset, and when controlling for other forms of offspring psychopathology. Each of these controls rules out alternative explanations for the association. The results of the current study converge with those of prior research in suggesting that factors directly associated with offspring ADHD increase parental marital problems.

Beyond greening and browning: the need for an integrated understanding of Arctic change

NASA Astrophysics Data System (ADS)

Gamon, J. A.; Huemmrich, K. F.; Hmimina, G.; Yu, R.

2017-12-01

Satellite records and field observations povide contradictory evidence for "greening" or "browning" of Arctic tundra. Large-scale observations of apparent greening have been based on satellite vegetation indices (e.g NDVI). However, a clear interpretation of these trends are confounded by changing snow cover and surface hydrology, both of which influence NDVI and are known to be changing independently of any direct vegetation response. Field studies have demonstrated greening in some areas, but not others, and have also documented changing permafrost depth, surface hydrology and snow cover. Together, these confounding factors can explain some of the contradictory evidence based regarding greening and browning. Given the multiple influences on Arctic NDVI, simple conclusions regarding greening and browning from satellite data alone can be incorrect; when these confounding factors are taken into account, some areas that show apparent greening in the satellite record appear to be undergoing productivity declines due to surface drying. These contradictory interpretations have profound implications for our understanding of changing surface energy balance, biogeochemistry, and surface-atmosphere feedbacks. To better address Arctic ecosystem responses to a changing climate, an integrated, multi-scale, multivariate approach that considers hydrology, permafrost, snow cover and vegetation is needed.

Offspring ADHD as a Risk Factor for Parental Marital Problems: Controls for Genetic and Environmental Confounds

PubMed Central

Schermerhorn, Alice C.; D’Onofrio, Brian M.; Slutske, Wendy S.; Emery, Robert E.; Turkheimer, Eric; Harden, K. Paige; Heath, Andrew C.; Martin, Nicholas G.

2013-01-01

Background Previous studies have found that child attention-deficit/hyperactivity disorder (ADHD) is associated with more parental marital problems. The reasons for this association are unclear, however. The association might be due to genetic or environmental confounds that contribute to both marital problems and ADHD. Method Data were drawn from the Australian Twin Registry, including 1296 individual twins, their spouses, and offspring. We studied adult twins who were discordant for offspring ADHD. Using a discordant twin pairs design, we examined the extent to which genetic and environmental confounds, as well as measured parental and offspring characteristics, explain the ADHD-marital problems association. Results Offspring ADHD predicted parental divorce and marital conflict. The associations were also robust when comparing differentially exposed identical twins to control for unmeasured genetic and environmental factors, when controlling for measured maternal and paternal psychopathology, when restricting the sample based on timing of parental divorce and ADHD onset, and when controlling for other forms of offspring psychopathology. Each of these controls rules out alternative explanations for the association. Conclusion The results of the current study converge with those of prior research in suggesting that factors directly associated with offspring ADHD increase parental marital problems. PMID:22958575

MicroRNA content in milk exosomes as a phenotypic indicator of Staphylococcus aureus infection in the bovine mammary gland

USDA-ARS?s Scientific Manuscript database

Previous gene mapping research to understand the host genetic response to mammary infection based on somatic cell score has been unsuccessful due to the poor correlation of this confounding trait with mastitis, a disease costing the dairy industry an estimated $2 billion in annual costs. Recently, ...

Gender Bias in the Diagnosis of a Geriatric Standardized Patient: A Potential Confounding Variable

ERIC Educational Resources Information Center

Lewis, Roya; Lamdan, Ruth M.; Wald, David; Curtis, Michael

2006-01-01

Background: Gender bias has been reported in the diagnosis and treatment of patients with a variety of illnesses. In the context of our 10-station fourth year Objective Structured Clinical Evaluation, we queried whether this could influence diagnosis in a geriatric case. Case writers hypothesized that, due to this bias, the female standardized…

[Association between particulate matter from biomass burning and respiratory diseases in the southern region of the Brazilian Amazon].

PubMed

do Carmo, Cleber Nascimento; Hacon, Sandra; Longo, Karla Maria; Freitas, Saulo; Ignotti, Eliane; Ponce de Leon, Antonio; Artaxo, Paulo

2010-01-01

To investigate the short-term effects of exposure to particulate matter from biomass burning in the Amazon on the daily demand for outpatient care due to respiratory diseases in children and the elderly. Epidemiologic study with ecologic time series design. Daily consultation records were obtained from the 14 primary health care clinics in the municipality of Alta Floresta, state of Mato Grosso, in the southern region of the Brazilian Amazon, between January 2004 and December 2005. Information on the daily levels of fine particulate matter was made available by the Brazilian National Institute for Spatial Research. To control for confounding factors (situations in which a non-causal association between exposure and disease is observed due to a third variable), variables related to time trends, seasonality, temperature, relative humidity, rainfall, and calendar effects (such as occurrence of holidays and weekends) were included in the model. Poisson regression with generalized additive models was used. A 10 microg/m3 increase in the level of exposure to particulate matter was associated with increases of 2.9% and 2.6% in outpatient consultations due to respiratory diseases in children on the 6th and 7th days following exposure. Significant associations were not observed for elderly individuals. The results suggest that the levels of particulate matter from biomass burning in the Amazon are associated with adverse effects on the respiratory health of children.

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.

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.

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.

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.

Safety of metformin in patients with chronic obstructive pulmonary disease and type 2 diabetes mellitus.

PubMed

Hitchings, Andrew W; Archer, John R H; Srivastava, Shelley A; Baker, Emma H

2015-04-01

Type 2 diabetes mellitus (T2DM) is commonly associated with chronic obstructive pulmonary disease (COPD). Metformin is a valuable treatment for T2DM, and may offer additional benefits in COPD. However, due to its rare association with lactic acidosis, its safety in COPD is uncertain. We retrospectively identified patients with T2DM who had been admitted to hospital for COPD exacerbations. We compared those who were taking metformin with those who were not, with respect to their lactate concentration (primary endpoint) and survival (secondary endpoint). The study cohort (n = 130) had a mean (±standard deviation) age of 73.0 ± 9.8 years and 47 (36%) were female. Arterial blood gases were recorded in 120 cases: 88 (73%) were hypoxemic, 45 (38%) were in respiratory failure and 33 (28%) had respiratory acidosis. The 51 patients (39%) in the metformin group had a median (interquartile range) lactate concentration of 1.45 mmol/L (1.10-2.05) versus 1.10 mmol/L (0.80-1.50) in the non-metformin group (p = 0.012). Median survival was 5.2 years (95% CI 4.5-5.8) versus 1.9 years (1.1-2.6), respectively (hazard ratio 0.57; 95% CI 0.35-0.94). This remained significant in a multivariate model adjusted for measurable confounders. In conclusion, among patients with COPD at high risk for lactate accumulation, metformin therapy was associated with a minor elevation of lactate concentration of doubtful clinical significance. Metformin was associated with a survival benefit, but this must be interpreted cautiously due to possible effects from unmeasured confounders. Viewed collectively, the results suggest that COPD should not present a barrier to the investigational or clinical use of metformin.

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.

Decreased pain sensitivity due to trimethylbenzene exposure ...

EPA Pesticide Factsheets

Traditionally, human health risk assessments have relied on qualitative approaches for hazard identification, often using the Hill criteria and weight of evidence determinations to integrate data from multiple studies. Recently, the National Research Council has recommended the development of quantitative approaches for evidence integration, including the application of meta-analyses. The following hazard identification case study applies qualitative as well as meta-analytic approaches to trimethylbenzene (TMB) isomers exposure and the potential neurotoxic effects on pain sensitivity. In the meta-analytic approach, a pooled effect size is calculated, after consideration of multiple confounding factors, in order to determine whether the entire database under consideration indicates that TMBs are likely to be a neurotoxic hazard. The pain sensitivity studies included in the present analyses initially seem discordant in their results: effects on pain sensitivity are seen immediately after termination of exposure, appear to resolve 24 hours after exposure, and then reappear 50 days later following foot-shock. Qualitative consideration of toxicological and toxicokinetic characteristics of the TMB isomers suggests that the observed differences between studies are due to testing time and can be explained through a complete consideration of the underlying biology of the effect and the nervous system as a whole. Meta-analyses and –regressions support this conclus

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.

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.

Discerning the role of optimism in persuasion: the valence-enhancement hypothesis.

PubMed

Geers, Andrew L; Handley, Ian M; McLarney, Amber R

2003-09-01

The valence-enhancement hypothesis argues that because of their active coping strategies, optimists are especially likely to elaborate on valenced information that is of high personal relevance. The hypothesis predicts that as a result, optimists will be more persuaded by personally relevant positive messages and less persuaded by personally relevant negative messages than pessimists. It also predicts that when the message is not personally relevant, optimism and persuasion will not be related in this manner. The results of 3 studies support these predictions and supply evidence against several alternative hypotheses. The possibility that the observed effects are not due to optimism but to the confounding influence of 7 additional variables is also addressed and ruled out. Implications are discussed.

Impact of maternal obesity on inhaled corticosteroid use in childhood: a registry based analysis of first born children and a sibling pair analysis.

PubMed

Lowe, Adrian J; Ekeus, Cecilia; Bråbäck, Lennart; Rajaleid, Kristiina; Forsberg, Bertil; Hjern, Anders

2013-01-01

It has been proposed that maternal obesity during pregnancy may increase the risk that the child develops allergic disease and asthma, although the mechanisms underpinning this relationship are currently unclear. We sought to assess if this association may be due to confounding by genetic or environmental risk factors that are common to maternal obesity and childhood asthma, using a sibling pair analysis. The study population comprised a Swedish national cohort of term children born between 1992 and 2008 to native Swedish parents. Maternal body mass index (BMI) was measured at 8-10 weeks gestation. Unconditional logistic regression models were used to determine if maternal obesity was associated with increased risk of inhaled corticosteroid (ICS) in 431,718 first-born children, while adjusting for potential confounders. An age-matched discordant sib-pair analysis was performed, taking into account shared genetic and environmental risk factors. Maternal over-weight and obesity were associated with increased risk that the child would require ICS (for BMI≥35 kg/m(2), aOR = 1.30, 95%CI = 1.10-1.52 compared with normal weight mothers) in children aged 6-12 years. Similar effects were seen in younger children, but in children aged 13-16 years, maternal obesity (BMI≥30) was related to increased risk of ICS use in girls (aOR = 1.28, 95%CI = 1.07-1.53) but not boys (OR = 1.05, 95%CI = 0.87-1.26). The sib-pair analysis, which included 2,034 sib-pairs older than six years who were discordant for both ICS use and maternal BMI category, failed to find any evidence that increasing maternal weight was related to increased risk of ICS use. Maternal obesity is associated with increased risk of childhood ICS use up to approximately 12 years of age, but only in girls after this age. These effects could not be confirmed in a sib pair analysis, suggesting either limited statistical power, or the effects of maternal BMI may be due to shared genetic or environmental risk factors.

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.

Patent Ductus Arteriosus Ligation and Adverse Outcomes: Causality or Bias?

PubMed Central

Weisz, Dany E.; McNamara, Patrick J.

2014-01-01

Observational studies have associated patent ductus arteriosus (PDA) ligation in preterm infants with increased chronic lung disease (CLD), retinopathy of prematurity, and neurodevelopmental impairment at long-term follow-up. Although the biological rationale for this association is incompletely understood, there is an emerging secular trend toward a permissive approach to the PDA. However, insufficient adjustment for postnatal, pre-ligation confounders, such as intraventricular hemorrhage and the duration and intensity of mechanical ventilation, suggests the presence of residual bias due to confounding by indication, and obliges caution in interpreting the ligation-morbidity relationship. A period of conservative management after failure of medical PDA closure may be considered to reduce the number of infants treated with surgery. Increased mortality and CLD in infants with persistent symptomatic PDA suggests that surgical ligation remains an important treatment modality for preterm infants. PMID:25024972

Clinical and evoked pain, personality traits, and emotional states: can familial confounding explain the associations?

PubMed

Strachan, Eric; Poeschla, Brian; Dansie, Elizabeth; Succop, Annemarie; Chopko, Laura; Afari, Niloofar

2015-01-01

Pain is a complex phenomenon influenced by context and person-specific factors. Affective dimensions of pain involve both enduring personality traits and fleeting emotional states. We examined how personality traits and emotional states are linked with clinical and evoked pain in a twin sample. 99 female twin pairs were evaluated for clinical and evoked pain using the McGill Pain Questionnaire (MPQ) and dolorimetry, and completed the 120-item International Personality Item Pool (IPIP), the Positive and Negative Affect Scale (PANAS), and ratings of stress and mood. Using a co-twin control design we examined a) the relationship of personality traits and emotional states with clinical and evoked pain and b) whether genetics and common environment (i.e. familial factors) may account for the associations. Neuroticism was associated with the sensory component of the MPQ; this relationship was not confounded by familial factors. None of the emotional state measures was associated with the MPQ. PANAS negative affect was associated with lower evoked pressure pain threshold and tolerance; these associations were confounded by familial factors. There were no associations between IPIP traits and evoked pain. A relationship exists between neuroticism and clinical pain that is not confounded by familial factors. There is no similar relationship between negative emotional states and clinical pain. In contrast, the relationship between negative emotional states and evoked pain is strong while the relationship with enduring personality traits is weak. The relationship between negative emotional states and evoked pain appears to be non-causal and due to familial factors. Copyright © 2014 Elsevier Inc. All rights reserved.

Maternal Pre-Pregnancy Body Mass Index and Offspring Temperament and Behavior at 1 and 2 Years of Age

ERIC Educational Resources Information Center

Van Lieshout, Ryan J.; Schmidt, Louis A.; Robinson, Monique; Niccols, Alison; Boyle, Michael H.

2013-01-01

Recent research suggests that fetal exposure to increased maternal body mass index (BMI) during pregnancy may be associated with psychopathology later in life. When this link first emerges, and if it is due to intrauterine exposures or confounding variables is not known. We therefore assessed associations between maternal pre-pregnancy BMI and:…

Approaches for Strengthening Causal Inference Regarding Prenatal Risk Factors for Childhood Behavioural and Psychiatric Disorders

ERIC Educational Resources Information Center

Lewis, Sarah J.; Relton, Caroline; Zammit, Stanley; Smith, George Davey

2013-01-01

Background: The risk of childhood behavioural and psychiatric diseases could be substantially reduced if modifiable risk factors for these disorders were identified. The critical period for many of these exposures is likely to be in utero as this is the time when brain development is most rapid. However, due to confounding and other limitations of…

Passage of Campylobacter jejuni and Campylobacter coli subtypes through 0.45 and 0.65 µm pore size nitro-cellulose filters

USDA-ARS?s Scientific Manuscript database

Campylobacter can be difficult to recover from complex samples due to overgrowth by background bacteria. A 0.45 or 0.65 µm pore size filter overlaid on agar plates can be used as a means to separate Campylobacter from confounding non-Campylobacter cells, facilitating detection on solid plating medi...

A Genetically Informed Study of the Processes Underlying the Association between Parental Marital Instability and Offspring Adjustment

ERIC Educational Resources Information Center

D'Onofrio, Brian M.; Turkheimer, Eric; Emery, Robert E.; Slutske, Wendy S.; Heath, Andrew C.; Madden, Pamela A.; Martin, Nicholas G.

2006-01-01

Parental divorce is associated with problematic offspring adjustment, but the relation may be due to shared genetic or environmental factors. One way to test for these confounds is to study offspring of twins discordant for divorce. The current analyses used this design to separate the mechanisms responsible for the association between parental…

Reactive Aggression and Peer Victimization from Pre-Kindergarten to First Grade: Accounting for Hyperactivity and Teacher-Child Conflict

ERIC Educational Resources Information Center

Runions, Kevin C.

2014-01-01

Background: The role of reactive aggression in the development of peer victimization remains unclear due in part to a failure to account for confounding problems of behavioural undercontrol (e.g., hyperactivity). As well, the school social context has rarely been examined to see whether these risks are mediated by relationships with teachers.…

Spatially random mortality in old-growth red pine forests of northern Minnesota

Treesearch

Tuomas ​Aakala; Shawn Fraver; Brian J. Palik; Anthony W. D' Amato

2012-01-01

Characterizing the spatial distribution of tree mortality is critical to understanding forest dynamics, but empirical studies on these patterns under old-growth conditions are rare. This rarity is due in part to low mortality rates in old-growth forests, the study of which necessitates long observation periods, and the confounding influence of tree in-growth during...

Register-based data of psychosocial working conditions and occupational groups as predictors of disability pension due to musculoskeletal diagnoses: a prospective cohort study of 24 543 Swedish twins

PubMed Central

2013-01-01

Background Occupations and psychosocial working conditions have rarely been investigated as predictors of disability pension in population-based samples. This study investigated how occupational groups and psychosocial working conditions are associated with future disability pension due to musculoskeletal diagnoses, accounting for familial factors in the associations. Methods A sample of 24 543 same-sex Swedish twin individuals was followed from 1993 to 2008 using nationwide registries. Baseline data on occupations were categorized into eight sector-defined occupational groups. These were further used to reflect psychosocial working conditions by applying the job strain scores of a Job Exposure Matrix. Cox proportional hazard ratios (HR) were estimated. Results During the 12-year (average) follow-up, 7% of the sample was granted disability pension due to musculoskeletal diagnoses. Workers in health care and social work; agriculture, forestry and fishing; transportation; production and mining; and the service and military work sectors were two to three times more likely to receive a disability pension than those in the administration and management sector. Each single unit decrease in job demands and each single unit increase in job control and social support significantly predicted disability pension. Individuals with high work strain or an active job had a lower hazard ratio of disability pension, whereas a passive job predicted a significantly higher hazard ratio. Accounting for familial confounding did not alter these results. Conclusion Occupational groups and psychosocial working conditions seem to be independent of familial confounding, and hence represent risk factors for disability pension due to musculoskeletal diagnoses. This means that preventive measures in these sector-defined occupational groups and specific psychosocial working conditions might prevent disability pension due to musculoskeletal diagnoses. PMID:24040914

Register-based data of psychosocial working conditions and occupational groups as predictors of disability pension due to musculoskeletal diagnoses: a prospective cohort study of 24,543 Swedish twins.

PubMed

Ropponen, Annina; Samuelsson, Åsa; Alexanderson, Kristina; Svedberg, Pia

2013-09-16

Occupations and psychosocial working conditions have rarely been investigated as predictors of disability pension in population-based samples. This study investigated how occupational groups and psychosocial working conditions are associated with future disability pension due to musculoskeletal diagnoses, accounting for familial factors in the associations. A sample of 24,543 same-sex Swedish twin individuals was followed from 1993 to 2008 using nationwide registries. Baseline data on occupations were categorized into eight sector-defined occupational groups. These were further used to reflect psychosocial working conditions by applying the job strain scores of a Job Exposure Matrix. Cox proportional hazard ratios (HR) were estimated. During the 12-year (average) follow-up, 7% of the sample was granted disability pension due to musculoskeletal diagnoses. Workers in health care and social work; agriculture, forestry and fishing; transportation; production and mining; and the service and military work sectors were two to three times more likely to receive a disability pension than those in the administration and management sector. Each single unit decrease in job demands and each single unit increase in job control and social support significantly predicted disability pension. Individuals with high work strain or an active job had a lower hazard ratio of disability pension, whereas a passive job predicted a significantly higher hazard ratio. Accounting for familial confounding did not alter these results. Occupational groups and psychosocial working conditions seem to be independent of familial confounding, and hence represent risk factors for disability pension due to musculoskeletal diagnoses. This means that preventive measures in these sector-defined occupational groups and specific psychosocial working conditions might prevent disability pension due to musculoskeletal diagnoses.

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.

Effects of caffeine on performance and mood: withdrawal reversal is the most plausible explanation.

PubMed

James, Jack E; Rogers, Peter J

2005-10-01

Although it is widely believed that caffeine can enhance human performance and mood, the validity of this belief has been questioned, giving rise to debate. The central question is whether superior performance and mood after caffeine represent net benefits, or whether differences between caffeine and control conditions are due to reversal of adverse withdrawal effects. To provide a focussed review of relevant experimental studies with the aim of clarifying current understanding regarding the effects of caffeine on human performance and mood. To avoid the shortcomings of standard placebo-controlled studies, which are ambiguous due to failure to control for the confounding influence of withdrawal reversal, three main experimental approaches have been employed: studies that compare consumers and low/non-consumers, pre-treatment and ad lib consumption studies, and long-term withdrawal studies. Of the three approaches, only long-term withdrawal studies are capable of unambiguously revealing the net effects of caffeine. Overall, there is little evidence of caffeine having beneficial effects on performance or mood under conditions of long-term caffeine use vs abstinence. Although modest acute effects may occur following initial use, tolerance to these effects appears to develop in the context of habitual use of the drug. Appropriately controlled studies show that the effects of caffeine on performance and mood, widely perceived to be net beneficial psychostimulant effects, are almost wholly attributable to reversal of adverse withdrawal effects associated with short periods of abstinence from the drug.

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.

Testing the Dose–Response Specification in Epidemiology: Public Health and Policy Consequences for Lead

PubMed Central

Rothenberg, Stephen J.; Rothenberg, Jesse C.

2005-01-01

Statistical evaluation of the dose–response function in lead epidemiology is rarely attempted. Economic evaluation of health benefits of lead reduction usually assumes a linear dose–response function, regardless of the outcome measure used. We reanalyzed a previously published study, an international pooled data set combining data from seven prospective lead studies examining contemporaneous blood lead effect on IQ (intelligence quotient) of 7-year-old children (n = 1,333). We constructed alternative linear multiple regression models with linear blood lead terms (linear–linear dose response) and natural-log–transformed blood lead terms (log-linear dose response). We tested the two lead specifications for nonlinearity in the models, compared the two lead specifications for significantly better fit to the data, and examined the effects of possible residual confounding on the functional form of the dose–response relationship. We found that a log-linear lead–IQ relationship was a significantly better fit than was a linear–linear relationship for IQ (p = 0.009), with little evidence of residual confounding of included model variables. We substituted the log-linear lead–IQ effect in a previously published health benefits model and found that the economic savings due to U.S. population lead decrease between 1976 and 1999 (from 17.1 μg/dL to 2.0 μg/dL) was 2.2 times ($319 billion) that calculated using a linear–linear dose–response function ($149 billion). The Centers for Disease Control and Prevention action limit of 10 μg/dL for children fails to protect against most damage and economic cost attributable to lead exposure. PMID:16140626

Empirical evaluation of data normalization methods for molecular classification

PubMed Central

Huang, Huei-Chung

2018-01-01

Background Data artifacts due to variations in experimental handling are ubiquitous in microarray studies, and they can lead to biased and irreproducible findings. A popular approach to correct for such artifacts is through post hoc data adjustment such as data normalization. Statistical methods for data normalization have been developed and evaluated primarily for the discovery of individual molecular biomarkers. Their performance has rarely been studied for the development of multi-marker molecular classifiers—an increasingly important application of microarrays in the era of personalized medicine. Methods In this study, we set out to evaluate the performance of three commonly used methods for data normalization in the context of molecular classification, using extensive simulations based on re-sampling from a unique pair of microRNA microarray datasets for the same set of samples. The data and code for our simulations are freely available as R packages at GitHub. Results In the presence of confounding handling effects, all three normalization methods tended to improve the accuracy of the classifier when evaluated in an independent test data. The level of improvement and the relative performance among the normalization methods depended on the relative level of molecular signal, the distributional pattern of handling effects (e.g., location shift vs scale change), and the statistical method used for building the classifier. In addition, cross-validation was associated with biased estimation of classification accuracy in the over-optimistic direction for all three normalization methods. Conclusion Normalization may improve the accuracy of molecular classification for data with confounding handling effects; however, it cannot circumvent the over-optimistic findings associated with cross-validation for assessing classification accuracy. PMID:29666754

Efficacy of acarbose in different geographical regions of the world: analysis of a real-life database.

PubMed

Weng, Jianping; Soegondo, Sidartawan; Schnell, Oliver; Sheu, Wayne H-H; Grzeszczak, Wladyslaw; Watada, Hirotaka; Yamamoto, Noriyuki; Kalra, Sanjay

2015-02-01

Alpha-glucosidase inhibitors are recommended in some international guidelines as first-line, second-line and third-line treatment options but are not used worldwide due to perceived greater effectiveness in Asians than Caucasians. Data from ten post-marketing non-interventional studies using acarbose, the most widely used alpha-glucosidase inhibitor, from 21 countries, provinces and country groups were pooled. Effects on glycated hemoglobin (HbA1c ) were analysed for four major ethnicity/region groups (European Caucasians and Asians from East, Southeast and South Asia) to identify differences in the response to acarbose. The safety and efficacy populations included 67 682 and 62 905 patients, respectively. Mean HbA1c in the total population decreased by 1.12 ± 1.31% at the 3-month visit from 8.4% at baseline (p < 0.0001). Reductions in HbA1c , fasting plasma glucose and post-prandial plasma glucose were greater in patients with higher baseline values. Acarbose was well tolerated, with few episodes of hypoglycemia (0.03%) and gastrointestinal adverse events (2.76%). Data from 30 730 Caucasians from Europe and Asians from three major regions of Asia with non-missing gender/age information and baseline/3-month HbA1c data were analysed by multivariable analyses of covariance. After adjustment for relevant baseline confounding factors, Southeast and East Asians had slightly better responses to acarbose than South Asians and European Caucasians; however, the differences were small. Acarbose was effective in both European Caucasians and Asians; however, after adjustment for baseline confounding factors, significant small differences in response favoured Southeast and East Asians. © 2014 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons, Ltd.

Voxel-wise motion artifacts in population-level whole-brain connectivity analysis of resting-state FMRI.

PubMed

Spisák, Tamás; Jakab, András; Kis, Sándor A; Opposits, Gábor; Aranyi, Csaba; Berényi, Ervin; Emri, Miklós

2014-01-01

Functional Magnetic Resonance Imaging (fMRI) based brain connectivity analysis maps the functional networks of the brain by estimating the degree of synchronous neuronal activity between brain regions. Recent studies have demonstrated that "resting-state" fMRI-based brain connectivity conclusions may be erroneous when motion artifacts have a differential effect on fMRI BOLD signals for between group comparisons. A potential explanation could be that in-scanner displacement, due to rotational components, is not spatially constant in the whole brain. However, this localized nature of motion artifacts is poorly understood and is rarely considered in brain connectivity studies. In this study, we initially demonstrate the local correspondence between head displacement and the changes in the resting-state fMRI BOLD signal. Than, we investigate how connectivity strength is affected by the population-level variation in the spatial pattern of regional displacement. We introduce Regional Displacement Interaction (RDI), a new covariate parameter set for second-level connectivity analysis and demonstrate its effectiveness in reducing motion related confounds in comparisons of groups with different voxel-vise displacement pattern and preprocessed using various nuisance regression methods. The effect of using RDI as second-level covariate is than demonstrated in autism-related group comparisons. The relationship between the proposed method and some of the prevailing subject-level nuisance regression techniques is evaluated. Our results show that, depending on experimental design, treating in-scanner head motion as a global confound may not be appropriate. The degree of displacement is highly variable among various brain regions, both within and between subjects. These regional differences bias correlation-based measures of brain connectivity. The inclusion of the proposed second-level covariate into the analysis successfully reduces artifactual motion-related group differences and preserves real neuronal differences, as demonstrated by the autism-related comparisons.

Proton pump inhibitors and the risk of hospitalisation for community-acquired pneumonia: replicated cohort studies with meta-analysis

PubMed Central

Filion, Kristian B; Chateau, Dan; Targownik, Laura E; Gershon, Andrea; Durand, Madeleine; Tamim, Hala; Teare, Gary F; Ravani, Pietro; Ernst, Pierre; Dormuth, Colin R

2014-01-01

Objective Previous observational studies suggest that the use of proton pump inhibitors (PPIs) may increase the risk of hospitalisation for community-acquired pneumonia (HCAP). However, the potential presence of confounding and protopathic biases limits the conclusions that can be drawn from these studies. Our objective was, therefore, to examine the risk of HCAP with PPIs prescribed prophylactically in new users of non-steroidal anti-inflammatory drugs (NSAIDs). Design We formed eight restricted cohorts of new users of NSAIDs, aged ≥40 years, using a common protocol in eight databases (Alberta, Saskatchewan, Manitoba, Ontario, Quebec, Nova Scotia, US MarketScan and the UK's General Practice Research Database (GPRD)). This specific patient population was studied to minimise bias due to unmeasured confounders. High-dimensional propensity scores were used to estimate site-specific adjusted ORs (aORs) for HCAP at 6 months in PPI patients compared with unexposed patients. Fixed-effects meta-analytic models were used to estimate overall effects across databases. Results Of the 4 238 504 new users of NSAIDs, 2.3% also started a PPI. The cumulative 6-month incidence of HCAP was 0.17% among patients prescribed PPIs and 0.12% in unexposed patients. After adjustment, PPIs were not associated with an increased risk of HCAP (aOR=1.05; 95% CI 0.89 to 1.25). Histamine-2 receptor antagonists yielded similar results (aOR=0.95, 95% CI  0.75 to 1.21). Conclusions Our study does not support the proposition of a pharmacological effect of gastric acid suppressors on the risk of HCAP. PMID:23856153

Particulate matter air pollution and liver cancer survival.

PubMed

Deng, Huiyu; Eckel, Sandrah P; Liu, Lihua; Lurmann, Frederick W; Cockburn, Myles G; Gilliland, Frank D

2017-08-15

Particulate matter (PM) air pollution exposure has been associated with cancer incidence and mortality especially with lung cancer. The liver is another organ possibly affected by PM due to its role in detoxifying xenobiotics absorbed from PM. Various studies have investigated the mechanistic pathways between inhaled pollutants and liver damage, cancer incidence, and tumor progression. However, little is known about the effects of PM on liver cancer survival. Twenty thousand, two hundred and twenty-one California Cancer Registry patients with hepatocellular carcinoma (HCC) diagnosed between 2000 and 2009 were used to examine the effect of exposure to ambient PM with diameter <2.5 μm (PM 2.5 ) on HCC survival. Cox proportional hazards models were used to estimate hazard ratios (HRs) relating PM 2.5 to all-cause and liver cancer-specific mortality linearly and nonlinearly-overall and stratified by stage at diagnosis (local, regional and distant)-adjusting for potential individual and geospatial confounders.PM 2.5 exposure after diagnosis was statistically significantly associated with HCC survival. After adjustment for potential confounders, the all-cause mortality HR associated with a 1 standard deviation (5.0 µg/m 3 ) increase in PM 2.5 was 1.18 (95% CI: 1.16-1.20); 1.31 (95% CI:1.26-1.35) for local stage, 1.19 (95% CI:1.14-1.23) for regional stage, and 1.05 (95% CI:1.01-1.10) for distant stage. These associations were nonlinear, with substantially larger HRs at higher exposures. The associations between liver cancer-specific mortality and PM 2.5 were slightly attenuated compared to all-cause mortality, but with the same patterns.Exposure to elevated PM 2.5 after the diagnosis of HCC may shorten survival, with larger effects at higher concentrations. © 2017 UICC.

Lower expression of glutamic acid decarboxylase 67 in the prefrontal cortex in schizophrenia: contribution of altered regulation by Zif268.

PubMed

Kimoto, Sohei; Bazmi, H Holly; Lewis, David A

2014-09-01

Cognitive deficits of schizophrenia may be due at least in part to lower expression of the 67-kDa isoform of glutamic acid decarboxylase (GAD67), a key enzyme for GABA synthesis, in the dorsolateral prefrontal cortex of individuals with schizophrenia. However, little is known about the molecular regulation of lower cortical GAD67 levels in schizophrenia. The GAD67 promoter region contains a conserved Zif268 binding site, and Zif268 activation is accompanied by increased GAD67 expression. Thus, altered expression of the immediate early gene Zif268 may contribute to lower levels of GAD67 mRNA in the dorsolateral prefrontal cortex in schizophrenia. The authors used polymerase chain reaction to quantify GAD67 and Zif268 mRNA levels in dorsolateral prefrontal cortex area 9 from 62 matched pairs of schizophrenia and healthy comparison subjects, and in situ hybridization to assess Zif268 expression at laminar and cellular levels of resolution. The effects of potentially confounding variables were assessed in human subjects, and the effects of antipsychotic treatments were tested in antipsychotic-exposed monkeys. The specificity of the Zif268 findings was assessed by quantifying mRNA levels for other immediate early genes. GAD67 and Zif268 mRNA levels were significantly lower and were positively correlated in the schizophrenia subjects. Both Zif268 mRNA-positive neuron density and Zif268 mRNA levels per neuron were significantly lower in the schizophrenia subjects. These findings were robust to the effects of the confounding variables examined and differed from other immediate early genes. Deficient Zif268 mRNA expression may contribute to lower cortical GAD67 levels in schizophrenia, suggesting a potential mechanistic basis for altered cortical GABA synthesis and impaired cognition in schizophrenia.

Temperature preference as an indicator of the chronic toxicity of cupric ions to Mozambique Tilapia

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

Welch, T.J.; Stauffer, J.R. Jr.; Morgan, R.P. II

1989-11-01

Evaluation of the effects of environmental contaminants on aquatic communities has focused primarily on acute bioassays. These bioassays provide rapid and reproducible concentration response curves based on death as an endpoint. In recent years, however, emphasis has shifted towards monitoring sublethal effects of toxicants. Temperature is an easily quantifiable parameter influencing both the behavior and survival of fishes. As poikilotherms, fish use behavioral responses to help regulate body temperature. Fish thermoregulatory behavior may be altered by various toxic substances. Some researchers found that a 24 hr exposure of sublethal concentrations of copper caused a significant decrease in preferred temperature ofmore » fathead minnows (Pimephales promelas), although the results were confounded due to variations in copper concentrations. In this study, the authors examined the feasibility of using acute temperature preference tests to assess the chronic toxicity of low concentrations of free cupric ions to Mozambique tilapia, Oreochromis mossambicus (Peters).« less

Local processes in preattentive feature detection.

PubMed

Bacon, W F; Egeth, H E

1991-02-01

Sagi and Julesz (1987) claimed that for a target to be detected preattentively, it must be within some small critical distance of a nontarget. The independent effects of separation and display size, which were confounded in the Sagi and Julesz experiments, were examined. Experiments 1 and 2 revealed that in tasks requiring search for a color-defined target, target-nontarget separation had no effect on reaction time (RT). Display size, however, was inversely related to RT. Experiment 3 ruled out the possibility that the decreasing function of RT with display size was due to arousal caused by higher display luminance. When nontarget grouping was inhibited, (Exp. 4) it was found that RT no longer decreased with increasing display size. This suggests that nontarget grouping may have been the cause of the improved performance at larger display sizes. Experiments 5 and 6 extended the results to line segments, the stimuli used by Sagi and Julesz.

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.

Smoking and subsequent risk of early retirement due to permanent disability.

PubMed

Husemoen, Lise Lotte N; Osler, Merete; Godtfredsen, Nina S; Prescott, Eva

2004-03-01

Smoking is the most important single preventable cause of a variety of common diseases, and a considerable share of premature death is attributable to smoking. Although the effects of smoking on morbidity and mortality are widely recognized, little is known about the impact of smoking on early retirement due to chronic disease. The objective of the study is to determine the effects of smoking behaviour on early retirement due to permanent disability in a large sample of the general population. Follow-up study based on data from three longitudinal population studies conducted in the Copenhagen area. The final study population comprised 9,053 persons, 5,623 men and 3,430 women. Endpoint was grant of disability pension in the period 1980-1985. Baseline information was obtained from a self-administered questionnaire. Information about disability pensions was obtained from Statistics Denmark. Data analysis was performed by univariate and multiple logistic regression analyses. Smoking was found to be strongly associated with the risk of being granted a disability pension after adjustment for various confounders. The risk increased with daily consumption reaching a maximum odds ratio of 5.66 (1.88-17.00) and 5.61 (2.11-14.92) in heavily smoking men and women, respectively, who were below age 60. Smokers are at considerably higher risk of early retirement due to chronic disease. In addition to the burden of disease, this leads to social and economic problems for the individual and has a significant economic impact on society.

Effects of environmental factors on child survival in Bangladesh: a case control study.

PubMed

Hoque, B A; Chakraborty, J; Chowdhury, J T; Chowdhury, U K; Ali, M; el Arifeen, S; Sack, R B

1999-03-01

The need for further studies on relationships between deaths and environmental variables has been reported in the literature. This case-control study was, therefore, carried out to find out the associations between several social and environmental variables and deaths of children due to infectious diseases such as those leading to diarrhoea, acute respiratory infection, measles and other diseases. Six hundred and twenty-five deaths (cases) and an equal number of matched living children (controls) aged 1-59 months, were studied in rural Matlab. An analysis of crude and adjusted odds ratio showed differential associations. Sources of drinking water, amount of stored water, conditions of latrines, number of persons sleeping with the child and the type of cooking site were statistically significantly associated with deaths due to infectious diseases after controlling for breast feeding, immunization, and the family size. Significant associations were also observed between: (i) the sources of drinking water and deaths due to ARI, and (ii) conditions of latrines and deaths due to diarrhoeal diseases, after controlling for the confounding variables. Several other environmental factors also showed associations with these various death groups, but they were not statistically significant. The size of the samples in death groups (small) and the prevalence of more or less homogeneous environmental health conditions probably diminished the magnitude of the effects. The results of the study reconfirm the importance of environmental health intervention in child survival, irrespective of breast-feeding, immunization, and selected social variables.

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.

Plasma processing conditions substantially influence circulating microRNA biomarker levels.

PubMed

Cheng, Heather H; Yi, Hye Son; Kim, Yeonju; Kroh, Evan M; Chien, Jason W; Eaton, Keith D; Goodman, Marc T; Tait, Jonathan F; Tewari, Muneesh; Pritchard, Colin C

2013-01-01

Circulating, cell-free microRNAs (miRNAs) are promising candidate biomarkers, but optimal conditions for processing blood specimens for miRNA measurement remain to be established. Our previous work showed that the majority of plasma miRNAs are likely blood cell-derived. In the course of profiling lung cancer cases versus healthy controls, we observed a broad increase in circulating miRNA levels in cases compared to controls and that higher miRNA expression correlated with higher platelet and particle counts. We therefore hypothesized that the quantity of residual platelets and microparticles remaining after plasma processing might impact miRNA measurements. To systematically investigate this, we subjected matched plasma from healthy individuals to stepwise processing with differential centrifugation and 0.22 µm filtration and performed miRNA profiling. We found a major effect on circulating miRNAs, with the majority (72%) of detectable miRNAs substantially affected by processing alone. Specifically, 10% of miRNAs showed 4-30x variation, 46% showed 30-1,000x variation, and 15% showed >1,000x variation in expression solely from processing. This was predominantly due to platelet contamination, which persisted despite using standard laboratory protocols. Importantly, we show that platelet contamination in archived samples could largely be eliminated by additional centrifugation, even in frozen samples stored for six years. To minimize confounding effects in microRNA biomarker studies, additional steps to limit platelet contamination for circulating miRNA biomarker studies are necessary. We provide specific practical recommendations to help minimize confounding variation attributable to plasma processing and platelet contamination.

Antidepressant sales and regional variations of suicide mortality in Germany.

PubMed

Blüml, Victor; Helbich, Marco; Mayr, Michael; Turnwald, Roland; Vyssoki, Benjamin; Lewitzka, Ute; Hartung, Sebastian; Plener, Paul L; Fegert, Jörg M; Kapusta, Nestor D

2017-04-01

Suicides account for over one million deaths per year worldwide with depression among the most important risk factors. Epidemiological research into the relationship between antidepressant utilization and suicide mortality has shown heterogeneous and contradictory results. Different methodological approaches and limitations could at least partially explain varying results. This is the first study assessing the association of suicide mortality and antidepressant sales across Germany using complex statistical approaches in order to control for possible confounding factors including spatial dependency of data. German suicide counts were analyzed on a district level (n = 402) utilizing ecological Poisson regressions within a hierarchical Bayesian framework. Due to significant spatial effects between adjacent districts spatial models were calculated in addition to a baseline non-spatial model. Models were adjusted for several confounders including socioeconomic variables, quality of psychosocial care, and depression prevalence. Separate analyses were performed for Eastern and Western Germany and for different classes of antidepressants (SSRIs and TCAs). Overall antidepressant sales were significantly negatively associated with suicide mortality in the non-spatial baseline model, while after adjusting for spatially structured and unstructured effects the association turned out to be insignificant. In sub-analyses, analogue results were found for SSRIs and TCAs separately. Suicide risk shows a distinct heterogeneous pattern with a pronounced relative risk in Southeast Germany. In conclusion, the results reflect the heterogeneous findings of previous studies on the association between suicide mortality and antidepressant sales and point to the complexity of this hypothesized link. Furthermore, the findings support tailored suicide preventive efforts within high risk areas. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mortality and prostate cancer risk in 19,598 men after surgery for benign prostatic hyperplasia.

PubMed

Holman, C D; Wisniewski, Z S; Semmens, J B; Rouse, I L; Bass, A J

1999-07-01

To examine postoperative mortality and prostate cancer risk after the first prostatectomy for benign prostatic hypertrophy over a 17-year period in a population-based cohort of men in Western Australia, using improved methods to adjust for comorbidity. The relative survival from death and prostate cancer incidence was calculated against the background population rates. The outcomes of transurethral resection of the prostate (TURP) and open prostatectomy (OP) were compared adjusting for calendar year, age, admission type and comorbidity using Cox regression. Fractional polynomials were used to take account of nonlinearity in confounder effects. At 10 years, the relative survival was 116.5% in TURP patients and 123.5% after OP. Adjusting only for confounding by age, calendar year and admission type, TURP had a higher mortality rate than OP (rate ratio, RR, 1. 20; 95% confidence interval 1.08-1.34). The RR fell to 1.10 (0.99-1. 23) after adjustment for comorbidity and to 1.07 (0.95-1.19) when accounting for nonlinearity. The relative survival from the incidence of prostate cancer at 10 years was 103.7% after TURP and 104.5% after OP. The RR adjusted for age and calendar year was 1.44 (0.94-2.21) for incidence and 1.37 (0.81-2.29) for prostate cancer mortality. There is at most a small and clinically unimportant excess mortality risk from TURP; any difference could be due to a protective effect of OP on the long-term risk of prostate cancer and a lower rate of repeat prostatectomy.

Evaluating statistical approaches to leverage large clinical datasets for uncovering therapeutic and adverse medication effects.

PubMed

Choi, Leena; Carroll, Robert J; Beck, Cole; Mosley, Jonathan D; Roden, Dan M; Denny, Joshua C; Van Driest, Sara L

2018-04-18

Phenome-wide association studies (PheWAS) have been used to discover many genotype-phenotype relationships and have the potential to identify therapeutic and adverse drug outcomes using longitudinal data within electronic health records (EHRs). However, the statistical methods for PheWAS applied to longitudinal EHR medication data have not been established. In this study, we developed methods to address two challenges faced with reuse of EHR for this purpose: confounding by indication, and low exposure and event rates. We used Monte Carlo simulation to assess propensity score (PS) methods, focusing on two of the most commonly used methods, PS matching and PS adjustment, to address confounding by indication. We also compared two logistic regression approaches (the default of Wald vs. Firth's penalized maximum likelihood, PML) to address complete separation due to sparse data with low exposure and event rates. PS adjustment resulted in greater power than propensity score matching, while controlling Type I error at 0.05. The PML method provided reasonable p-values, even in cases with complete separation, with well controlled Type I error rates. Using PS adjustment and the PML method, we identify novel latent drug effects in pediatric patients exposed to two common antibiotic drugs, ampicillin and gentamicin. R packages PheWAS and EHR are available at https://github.com/PheWAS/PheWAS and at CRAN (https://www.r-project.org/), respectively. The R script for data processing and the main analysis is available at https://github.com/choileena/EHR. leena.choi@vanderbilt.edu. Supplementary data are available at Bioinformatics online.

Intelligence in youth and all-cause-mortality: systematic review with meta-analysis

PubMed Central

Calvin, Catherine M; Deary, Ian J; Fenton, Candida; Roberts, Beverly A; Der, Geoff; Leckenby, Nicola; Batty, G David

2011-01-01

Background A number of prospective cohort studies have examined the association between intelligence in childhood or youth and life expectancy in adulthood; however, the effect size of this association is yet to be quantified and previous reviews require updating. Methods The systematic review included an electronic search of EMBASE, MEDLINE and PSYCHINFO databases. This yielded 16 unrelated studies that met inclusion criteria, comprising 22 453 deaths among 1 107 022 participants. Heterogeneity was assessed, and fixed effects models were applied to the aggregate data. Publication bias was evaluated, and sensitivity analyses were conducted. Results A 1-standard deviation (SD) advantage in cognitive test scores was associated with a 24% (95% confidence interval 23–25) lower risk of death, during a 17- to 69-year follow-up. There was little evidence of publication bias (Egger’s intercept = 0.10, P = 0.81), and the intelligence–mortality association was similar for men and women. Adjustment for childhood socio-economic status (SES) in the nine studies containing these data had almost no impact on this relationship, suggesting that this is not a confounder of the intelligence–mortality association. Controlling for adult SES in five studies and for education in six studies attenuated the intelligence–mortality hazard ratios by 34 and 54%, respectively. Conclusions Future investigations should address the extent to which attenuation of the intelligence–mortality link by adult SES indicators is due to mediation, over-adjustment and/or confounding. The explanation(s) for association between higher early-life intelligence and lower risk of adult mortality require further elucidation. PMID:21037248

Intelligence in youth and all-cause-mortality: systematic review with meta-analysis.

PubMed

Calvin, Catherine M; Deary, Ian J; Fenton, Candida; Roberts, Beverly A; Der, Geoff; Leckenby, Nicola; Batty, G David

2011-06-01

A number of prospective cohort studies have examined the association between intelligence in childhood or youth and life expectancy in adulthood; however, the effect size of this association is yet to be quantified and previous reviews require updating. The systematic review included an electronic search of EMBASE, MEDLINE and PSYCHINFO databases. This yielded 16 unrelated studies that met inclusion criteria, comprising 22,453 deaths among 1,107,022 participants. Heterogeneity was assessed, and fixed effects models were applied to the aggregate data. Publication bias was evaluated, and sensitivity analyses were conducted. A 1-standard deviation (SD) advantage in cognitive test scores was associated with a 24% (95% confidence interval 23-25) lower risk of death, during a 17- to 69-year follow-up. There was little evidence of publication bias (Egger's intercept = 0.10, P = 0.81), and the intelligence-mortality association was similar for men and women. Adjustment for childhood socio-economic status (SES) in the nine studies containing these data had almost no impact on this relationship, suggesting that this is not a confounder of the intelligence-mortality association. Controlling for adult SES in five studies and for education in six studies attenuated the intelligence-mortality hazard ratios by 34 and 54%, respectively. Future investigations should address the extent to which attenuation of the intelligence-mortality link by adult SES indicators is due to mediation, over-adjustment and/or confounding. The explanation(s) for association between higher early-life intelligence and lower risk of adult mortality require further elucidation.

Entorhinal Cortex Volume in Antipsychotic-naïve Schizophrenia.

PubMed

Jose, Sam P; Sharma, Eesha; Narayanaswamy, Janardhanan C; Rajendran, Vishnurajan; Kalmady, Sunil V; Rao, Naren P; Venkatasubramanian, Ganesan; Gangadhar, Bangalore N

2012-04-01

Entorhinal cortex (ERC), a multimodal sensory relay station for the hippocampus, is critically involved in learning, emotion, and novelty detection. One of the pathogenetic mechanistic bases in schizophrenia is proposed to involve aberrant information processing in the ERC. Several studies have looked at cytoarchitectural and morphometric changes in the ERC, but results have been inconsistent possibly due to the potential confounding effects of antipsychotic treatment. In this study, we have examined the entorhinal cortex volume in antipsychotic-naïve schizophrenia patients (n=40; M:F=22:18) in comparison with age, sex, and handedness, matched (as a group) with healthy subjects (n=42; M:F=25:17) using a valid method. 3-Tesla MR images with 1-mm sections were used and the data was analyzed using the SPSS software. Female schizophrenia patients (1.25±0.22 mL) showed significant volume deficit in the right ERC in comparison with female healthy controls (1.45±0.34 mL) (F=4.9; P=0.03), after controlling for the potential confounding effects of intracranial volume. However, male patients did not differ from male controls. The left ERC volume did not differ between patients and controls. Consistent with the findings of a few earlier studies we found a reduction in the right ERC volume in patients. However, this was limited to women. Contextually, our study finding supports the role for ERC deficit in schizophrenia pathogenesis - perhaps mediated through aberrant novelty detection. Sex-differential observation of ERC volume deficit in schizophrenia needs further studies.

The effect of heartburn and acid reflux on the severity of nausea and vomiting of pregnancy

PubMed Central

Gill, Simerpal Kaur; Maltepe, Caroline; Koren, Gideon

2009-01-01

BACKGROUND: Heartburn (HB) and acid reflux (RF) in the non-pregnant population can cause nausea and vomiting; therefore, it is plausible that in women with nausea and vomiting of pregnancy (NVP), HB/RF may increase the severity of symptoms. OBJECTIVE: To determine whether HB/RF during pregnancy contribute to increased severity of NVP. METHODS: A prospectively collected cohort of women who were experiencing NVP and HB, RF or both (n=194) was studied. The Pregnancy-Unique Quantification of Emesis and Nausea (PUQE) scale and its Well-being scale was used to compare the severity of the study cohort’s symptoms. This cohort was compared with a group of women experiencing NVP but no HB/RF (n=188). Multiple linear regression was used to control for the effects of confounding factors. RESULTS: Women with HB/RF reported higher PUQE scores (9.6±2.6) compared with controls (8.9±2.6) (P=0.02). Similarly, Well-being scores for women experiencing HB/RF were lower (4.3±2.1) compared with controls (4.9±2.0) (P=0.01). Multiple linear regression analysis demonstrated that increased PUQE scores (P=0.003) and decreased Well-being scores (P=0.005) were due to the presence of HB/RF as opposed to confounding factors such as pre-existing gastrointestinal conditions/symptoms, hyperemesis gravidarum in previous pregnancies and comorbidities. CONCLUSION: The present cohort study is the first to demonstrate that HB/RF are associated with increased severity of NVP. Managing HB/RF may improve the severity of NVP. PMID:19373420

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.

The effects of riverine physical complexity on anadromy and genetic diversity in steelhead or rainbow trout Oncorhynchus mykiss around the Pacific Rim.

PubMed

McPhee, M V; Whited, D C; Kuzishchin, K V; Stanford, J A

2014-07-01

This study explored the relationship between riverine physical complexity, as determined from remotely sensed metrics, and anadromy and genetic diversity in steelhead or rainbow trout Oncorhynchus mykiss. The proportion of anadromy (estimated fraction of individuals within a drainage that are anadromous) was correlated with riverine complexity, but this correlation appeared to be driven largely by a confounding negative relationship between drainage area and the proportion of anadromy. Genetic diversity decreased with latitude, was lower in rivers with only non-anadromous individuals and also decreased with an increasing ratio of floodplain area to total drainage area. Anadromy may be less frequent in larger drainages due to the higher cost of migration associated with reaches farther from the ocean, and the negative relationship between genetic diversity and floodplain area may be due to lower effective population size resulting from greater population fluctuations associated with higher rates of habitat turnover. Ultimately, the relationships between riverine physical complexity and migratory life history or genetic diversity probably depend on the spatial scale of analysis. © 2014 The Fisheries Society of the British Isles.

Meat intake and reproductive parameters among young men

PubMed Central

Afeiche, Myriam C; Williams, Paige L; Gaskins, Audrey J; Mendiola, Jaime; Jørgensen, Niels; Swan, Shanna H

2014-01-01

Background In the United States, anabolic sex steroids are administered to cattle for growth promotion. There is concern regarding the reproductive consequences of this practice for men who eat beef. We investigated whether meat consumption was associated with semen quality parameters and reproductive hormone levels in young men. Methods Semen samples were obtained from 189 men aged 18-22 years. Diet was assessed with a previously validated food frequency questionnaire. We used linear regression to analyze the cross-sectional associations of meat intake with semen quality parameters and reproductive hormones, while adjusting for potential confounders. Results There was an inverse relation between processed red meat intake and total sperm count. The adjusted relative differences in total sperm counts for men in increasing quartiles of processed meat intake were 0 (ref), −3 (95% confidence interval = −67 to 37), −14 (−82 to 28), and −78 (−202 to −5) million (test for trend, P = 0.01). This association was strongest among men with abstinence time less than 2 days and was driven by a strong inverse relation between processed red meat intake and ejaculate volume (test for trend, P =0.003). Conclusions In our population of young men, processed meat intake was associated with lower total sperm count. We cannot distinguish whether this association is due to residual confounding by abstinence time or represents a true biological effect. PMID:24681577

Birth Weight, Physical Morbidity, and Mortality: A Population-based Sibling-Comparison Study

PubMed Central

Class, Quetzal A.; Rickert, Martin E.; Lichtenstein, Paul; D'Onofrio, Brian M.

2014-01-01

Associations between low birth weight (≤2,500 g) and increased risk of mortality and morbidity provided the foundation for the “developmental origins of health and disease” hypothesis. Previous between-family studies could not control for unmeasured confounders. Therefore, we compared differentially exposed siblings to estimate the extent to which the associations were due to uncontrolled factors. Our population cohort included 3,291,773 persons born in Sweden from 1973 to 2008. Analyses controlled for gestational age, among other covariates, and considered birth weight as both an ordinal and a continuous variable. Outcomes included mortality after 1 year, cardiac-related death, hypertension, ischemic heart disease, pulmonary circulation problems, stroke, and type 2 diabetes mellitus. We fitted fixed-effects models to compare siblings and conducted sensitivity analyses to test alternative explanations. Across the population, the lower the birth weight, the greater the risk of mortality (e.g., cardiac-related death (low birth weight hazard ratio = 2.69, 95% confidence interval: 2.05, 3.53)) and morbidity (e.g., type 2 diabetes mellitus (low birth weight hazard ratio = 1.79, 95% confidence interval: 1.50, 2.14)) outcomes in comparison with normal birth weight. All associations were independent of shared familial confounders and measured covariates. Results emphasize the importance of birth weight as a risk factor for subsequent mortality and morbidity. PMID:24355331

The Development of Extremely Preterm Infants Born to Women Who Had Genitourinary Infections During Pregnancy

PubMed Central

Leviton, Alan; Allred, Elizabeth N.; Kuban, Karl C. K.; O'Shea, T. Michael; Paneth, Nigel; Onderdonk, Andrew B.; Fichorova, Raina N.; Dammann, Olaf

2016-01-01

Gestational genitourinary infections, which have been associated with neurodevelopmental impairments among infants born near term, have not been studied among very preterm infants. The mothers of 989 infants born before 28 weeks of gestation were interviewed about urine, bladder, or kidney infections (UTIs) and cervical or vaginal infections (CVIs) during pregnancy, as well as other exposures and characteristics, and their charts were reviewed for the Extremely Low Gestational Age Newborns (ELGAN) Study (2002–2004). At 2 years of age, these infants underwent a neurodevelopmental assessment. Generalized estimating equation logistic regression models of developmental adversities were used to adjust for potential confounders. Infants born to women who reported a UTI were less likely than were others to have a very low Mental Development Index (adjusted odds ratio = 0.5; 95% confidence interval: 0.3, 0.8), whereas infants born to women who reported a CVI were more likely than others to have a low Psychomotor Development Index (adjusted odds ratio = 1.7; 95% confidence interval: 1.04, 2.7). In this high-risk sample, maternal gestational CVI, but not UTI, was associated with a higher risk of impaired motor development at 2 years of age. The apparent protective effect of UTI might be spurious, reflect confounding due to untreated asymptomatic bacteriuria among women who were not given a diagnosis of UTI, or reflect preconditioning. PMID:26667255

Bone health of the Ovahimba people of north-western Namibia in the context of urbanization and a change of the sociocultural environment.

PubMed

Wilhelm, Anneke; Hadji, Peyman; Münzel, Mark; Daniel, Hanna; Flache, Stephan; Nyarango, Peter; Kann, Peter Herbert

2017-04-01

The prevalence of osteoporosis in Sub-Saharan African (SSA) countries is low, however, as urbanization takes root, it is predicted that bone health will decrease dramatically. The bone health of the semi-nomadic Ovahimba people of Namibia was investigated in the context of urbanization and changes of the sociocultural environment. Furthermore, data on bone health in SSA countries is scarce; there exists no ethnic-specific reference group for people of black origin. Included in the study were 98 urban and rural living Ovahimba people. Quantitative ultrasound was performed, sunrise/sunset saliva cortisol concentrations was measured and a questionnaire was conducted. There was no significant difference in the QUS parameters, however, after adjustment for confounders, SOS and SI differed significantly. The saliva cortisol concentrations differed significantly. After adjustment for confounders, saliva cortisol was significantly negatively correlated to SOS (r= -0.27, p = 0.021) giving an indication for an association between cortisol concentration and QUS parameters. The urban group furthermore showed a nutritional transition. Even though the bone health of the Ovahimba is very good, first signs of the adverse effects of urbanization were detected. Beside changes of lifestyle, this may be attributed to an increased cortisol exposure of the Ovahimba people living in an urban environment due to an increased psychosocial stress.

Letter to the editor concerning the article "Effects of acoustic feedback training in elite-standard Para-Rowing" by Schaffert and Mattes (2015).

PubMed

Hill, Holger

2015-01-01

In a case study, Schaffert and Mattes reported the application of acoustic feedback (sonification) to optimise the time course of boat acceleration. The authors attributed an increased boat speed in the feedback condition to an optimised boat acceleration (mainly during the recovery phase). However, in rowing it is biomechanically impossible to increase the boat speed significantly by reducing the fluctuations in boat acceleration during the rowing cycle. To assess such a, potentially small, optimising effect experimentally, the confounding variables must be controlled very accurately (that is especially the propulsive forces must be kept constant between experimental conditions or the differences in propulsive forces between conditions must be much smaller than the effects on boat speed resulting from an optimised movement pattern). However, this was not controlled adequately by the authors. Instead, the presented boat acceleration data show that the increased boat speed under acoustic feedback was due to increased propulsive forces.

Evaluating disease management program effectiveness: an introduction to survival analysis.

PubMed

Linden, Ariel; Adams, John L; Roberts, Nancy

2004-01-01

Currently, the most widely used method in the disease management industry for evaluating program effectiveness is the "total population approach." This model is a pretest-posttest design, with the most basic limitation being that without a control group, there may be sources of bias and/or competing extraneous confounding factors that offer plausible rationale explaining the change from baseline. Survival analysis allows for the inclusion of data from censored cases, those subjects who either "survived" the program without experiencing the event (e.g., achievement of target clinical levels, hospitalization) or left the program prematurely, due to disenrollement from the health plan or program, or were lost to follow-up. Additionally, independent variables may be included in the model to help explain the variability in the outcome measure. In order to maximize the potential of this statistical method, validity of the model and research design must be assured. This paper reviews survival analysis as an alternative, and more appropriate, approach to evaluating DM program effectiveness than the current total population approach.

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

Democratization and life expectancy in Europe, 1960-2008.

PubMed

Mackenbach, Johan P; Hu, Yannan; Looman, Caspar W N

2013-09-01

Over the past five decades, two successive waves of political reform have brought democracy to, first, Spain, Portugal and Greece, and, more recently, Central and Eastern European countries. We assessed whether democratization was associated with improvements in population health, as indicated by life expectancy and cause-specific mortality rates. Data on life expectancy at birth, age-standardized total and cause-specific mortality rates, levels of democracy and potential time-variant confounding variables were collected from harmonized international databanks. In two pooled cross-sectional time-series analyses with country-fixed effects, life expectancy and cause-specific mortality were regressed on measures of current and cumulative democracy, controlling for confounders. A first analysis covered the 1960-1990 period, a second covered the 1987-2008 period. In the 1960-1990 period, current democracy was more strongly associated with higher life expectancy than cumulative democracy. The positive effects of current democracy on total mortality were mediated mainly by lower mortality from heart disease, pneumonia, liver cirrhosis, and suicide. In the 1987-2008 period, however, current democracy was associated with lower, and cumulative democracy with higher life expectancy, particularly among men. The positive effects of cumulative democracy on total mortality were mediated mainly by lower mortality from circulatory diseases, cancer of the breast, and external causes. Current democracy was associated with higher mortality from motor vehicle accidents in both periods, and also with higher mortality from cancer and all external causes in the second. Our results suggest that in Europe during these two periods democratization has had mixed effects. That short-term changes in levels of democracy had positive effects in the first but not in the second period is probably due to the fact that democratization in Central and Eastern Europe was part of a complete system change which caused major societal disruptions. Copyright © 2013 Elsevier Ltd. All rights reserved.

CoAIMs: A Cost-Effective Panel of Ancestry Informative Markers for Determining Continental Origins

PubMed Central

Londin, Eric R.; Keller, Margaret A.; Maista, Cathleen; Smith, Gretchen; Mamounas, Laura A.; Zhang, Ran; Madore, Steven J.; Gwinn, Katrina; Corriveau, Roderick A.

2010-01-01

Background Genetic ancestry is known to impact outcomes of genotype-phenotype studies that are designed to identify risk for common diseases in human populations. Failure to control for population stratification due to genetic ancestry can significantly confound results of disease association studies. Moreover, ancestry is a critical factor in assessing lifetime risk of disease, and can play an important role in optimizing treatment. As modern medicine moves towards using personal genetic information for clinical applications, it is important to determine genetic ancestry in an accurate, cost-effective and efficient manner. Self-identified race is a common method used to track and control for population stratification; however, social constructs of race are not necessarily informative for genetic applications. The use of ancestry informative markers (AIMs) is a more accurate method for determining genetic ancestry for the purposes of population stratification. Methodology/Principal Findings Here we introduce a novel panel of 36 microsatellite (MSAT) AIMs that determines continental admixture proportions. This panel, which we have named Continental Ancestry Informative Markers or CoAIMs, consists of MSAT AIMs that were chosen based upon their measure of genetic variance (Fst), allele frequencies and their suitability for efficient genotyping. Genotype analysis using CoAIMs along with a Bayesian clustering method (STRUCTURE) is able to discern continental origins including Europe/Middle East (Caucasians), East Asia, Africa, Native America, and Oceania. In addition to determining continental ancestry for individuals without significant admixture, we applied CoAIMs to ascertain admixture proportions of individuals of self declared race. Conclusion/Significance CoAIMs can be used to efficiently and effectively determine continental admixture proportions in a sample set. The CoAIMs panel is a valuable resource for genetic researchers performing case-control genetic association studies, as it can control for the confounding effects of population stratification. The MSAT-based approach used here has potential for broad applicability as a cost effective tool toward determining admixture proportions. PMID:20976178

Twins' risk of childhood asthma mediated by gestational age and birthweight.

PubMed

Ullemar, V; Lundholm, C; Almqvist, C

2015-08-01

Children born with low gestational age (GA) or low birthweight (BW) are at increased risk of asthma. Twins as compared to singletons are on average more likely to be born with lower GA and BW and have been hypothesized to comprise a high-risk population for asthma. Many previous studies have not accounted for potential confounders or mediators. To investigate the association between twinship and childhood asthma or early life wheeze and identify potential mediators, such as GA/BW. The study population consisted of two cohorts including all children born in Sweden from 1 January 1993 to 1 June 2001 (n = 756,363 singletons, n = 22,478 twins) and 1 July 2005 to 31 December 2009 (n = 456,239 singletons, n = 12,872 twins). Asthma was defined using validated register-based outcomes of diagnosis or medication. The data were analysed using logistic (older cohort) and Cox regression (younger cohort). Adjusted models incorporated potential confounding or mediating factors including gestational age and birthweight. In the younger cohort, the crude hazard ratio (HR) of asthma medication after 1.5 years of age was 1.12 (95% CI 1.01-1.23), and fully adjusted HR was 0.80, 95% CI 0.72-0.89. Crude HR of asthma diagnosis in the same age group was 1.14 (95% CI 0.99-1.30), fully adjusted 0.78 (0.68-0.98). Adjusted analyses in the older group yielded similar results. Twins were at significantly higher unadjusted risk of asthma or early life wheeze compared to singletons in the younger, but not in the older cohort. Associations attenuated following adjustment for GA/BW, suggesting that GA/BW mediates the effect of twinship on asthma risk. After adjustments, twins were at lower risk of asthma outcomes, possibly due to unmeasured confounding. © 2015 John Wiley & Sons Ltd.

Type A personality, hostility, time urgency and unintentional injuries among Chinese undergraduates: a matched case–control study

PubMed Central

2013-01-01

Background Associations between type A behaviour pattern (TABP) and injuries are inconsistent. These inconsistencies may be due to different effects of various components of TABP, namely time urgency/impatience, hostility and competitive drive. It is important to examine the relationship between the global TABP, its two components, and unintentional injuries, among undergraduates in China. Methods On the basis of a previous cross-sectional study, we conducted a matched case–control study. 253 cases and an equal number of age-, gender-, and major-matched controls were included. The questionnaire solicited socio-demographic information, the experience of injuries, the scale of TABP, and other potential confounding factors. Besides the correlation between the global TABP and injuries, the influences of the two components of TABP on injuries were also evaluated. Conditional logistic regression was used to determine the crude odds ratios (ORs) and adjusted ORs of injury events. Results A dose–response relationship was apparent among students who rated themselves higher on the TABP scale (P-value for trend, 0.002), with a crude OR of 2.93 (95% CI: 0.93–9.19) for injuries comparing those with TABP to those with type B behaviour pattern (TBBP). After adjustment for potential confounding factors, TABP remained statistically significant, and the adjusted OR was 5.52 (95% CI: 1.43–21.27); from a comparison of students with TABP to those with TBBP. A dose–response relationship was also apparent between the hostility component and nonfatal injuries, both in crude analysis and after adjusting for other confounders. The relationship between time-hurry and injuries was not statistically significant, based on univariate and multivariate analyses. Conclusions Both the global TABP and the hostility component were associated with a dose response increase in the risk of non-fatal unintentional injuries among Chinese undergraduates. Further studies need to be conducted to confirm or reject this correlation. PMID:24219492

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.

The association of health-related fitness with indicators of academic performance in Texas schools.

PubMed

Welk, Gregory J; Jackson, Allen W; Morrow, James R; Haskell, William H; Meredith, Marilu D; Cooper, Kenneth H

2010-09-01

This study examined the associations between indicators of health-related physical fitness (cardiovascular fitness and body mass index) and academic performance (Texas Assessment of Knowledge and Skills). Partial correlations were generally stronger for cardiovascular fitness than body mass index and consistently stronger in the middle school grades. Mixed-model regression analyses revealed modest associations between fitness and academic achievement after controlling for potentially confounding variables. The effects of fitness on academic achievement were positive but small. A separate logistic regression analysis indicated that higher fitness rates increased the odds of schools achieving exemplary/recognized school status within the state. School fitness attainment is an indicator of higher performing schools. Direction of causality cannot be inferred due to the cross-sectional nature of the data.

Unrealistic comparative optimism: An unsuccessful search for evidence of a genuinely motivational bias.

PubMed

Harris, Adam J L; de Molière, Laura; Soh, Melinda; Hahn, Ulrike

2017-01-01

One of the most accepted findings across psychology is that people are unrealistically optimistic in their judgments of comparative risk concerning future life events-they judge negative events as less likely to happen to themselves than to the average person. Harris and Hahn (2011), however, demonstrated how unbiased (non-optimistic) responses can result in data patterns commonly interpreted as indicative of optimism due to statistical artifacts. In the current paper, we report the results of 5 studies that control for these statistical confounds and observe no evidence for residual unrealistic optimism, even observing a 'severity effect' whereby severe outcomes were overestimated relative to neutral ones (Studies 3 & 4). We conclude that there is no evidence supporting an optimism interpretation of previous results using the prevalent comparison method.

Concordant, non-atypical breast papillomas do not require surgical excision: A 10-year multi-institution study and review of the literature.

PubMed

Grimm, Lars J; Bookhout, Christine E; Bentley, Rex C; Jordan, Sheryl G; Lawton, Thomas J

2018-05-01

Non-atypical papillomas (NAPs) diagnosed on core needle biopsy (CNB) frequently undergo surgical excision due to highly variable upstaging rates. The purpose of this study is to document our dual-institution upgrade rates of NAPs diagnosed on core needle biopsy and review the upgrade rates reported in the literature. Following IRB approval, CNB results from Duke University (7/1/2004-6/30/2014) and the University of North Carolina Chapel Hill (1/1/04-6/30/2013) were reviewed to identify non-atypical papillomas. All cases with surgical excision or 2 years of imaging follow up were included. In addition, a literature review identified 60 published studies on upgrades of NAPs diagnosed at CNB. Cases in our cohort and the published literature were reviewed for confounding factors: [1] missing radiologic-pathologic concordance and/or discordance, [2] papillomas included with high-risk lesions, [3] high risk lesions counted as upgrades, [4] review by a nonspecialized breast pathologist, and [5] cancer incidentally detected. Of the 388 CNBs in our dual-institution cohort, 136 (35%) patients underwent surgical excision and 252 (65%) patients had imaging follow up. After controlling for confounders, no cancers (0/388) were found at surgical excision or during follow up imaging. The literature review upstaging rate was 4.0% (166/4157) but 1.8% (4/227) after excluding studies with confounders. The combined upstaging rate from the literature and this study was 0.6% (4/615). The upstaging rate for CNB diagnosed NAPs was 0% in our cohort and 0.6% overall after adjusting for confounders. This low rate does not warrant reflexive surgical excision and diagnostic imaging follow up should be discretionary. Copyright © 2018 Elsevier Inc. All rights reserved.

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.

Neurophysiological mechanism of possibly confounding peripheral activation of the facial nerve during corticobulbar tract monitoring.

PubMed

Téllez, Maria J; Ulkatan, Sedat; Urriza, Javier; Arranz-Arranz, Beatriz; Deletis, Vedran

2016-02-01

To improve the recognition and possibly prevent confounding peripheral activation of the facial nerve caused by leaking transcranial electrical stimulation (TES) current during corticobulbar tract monitoring. We applied a single stimulus and a short train of electrical stimuli directly to the extracranial portion of the facial nerve. We compared the peripherally elicited compound muscle action potential (CMAP) of the facial nerve with the responses elicited by TES during intraoperative monitoring of the corticobulbar tract. A single stimulus applied directly to the facial nerve at subthreshold intensities did not evoke a CMAP, whereas short trains of subthreshold stimuli repeatedly evoked CMAPs. This is due to the phenomenon of sub- or near-threshold super excitability of the cranial nerve. Therefore, the facial responses evoked by short trains TES, when the leaked current reaches the facial nerve at sub- or near-threshold intensity, could lead to false interpretation. Our results revealed a potential pitfall in the current methodology for facial corticobulbar tract monitoring that is due to the activation of the facial nerve by subthreshold trains of stimuli. This study proposes a new criterion to exclude peripheral activation during corticobulbar tract monitoring. The failure to recognize and avoid facial nerve activation due to leaking current in the peripheral portion of the facial nerve during TES decreases the reliability of corticobulbar tract monitoring by increasing the possibility of false interpretation. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Effects of combined vitamin D--calcium supplements on the cardiovascular system: should we be cautious?

PubMed

Challoumas, Dimitrios; Stavrou, Antonio; Pericleous, Agamemnon; Dimitrakakis, Georgios

2015-02-01

Despite the growing body of evidence on the potential effects of calcium and vitamin D as monotherapies on different cardiovascular (CV) parameters, the combined supplementation with calcium and vitamin D (CaD), which is most frequently encountered in clinical practice, has not received the attention it deserves. A literature search was conducted via EMBASE and Medline and identified 14 randomised controlled trials (RCTs) and 2 meta-analyses reporting on effects of combined supplementation with CaD on CV events, CV death, blood pressure, lipids, glucose metabolism and weight. Overall, the existing evidence does not support beneficial properties of supplementation with CaD on the CV system, nor does it suggest that a re-appraisal of the use of CaD is necessary due to adverse effects, although increased risk of CV events has been reported by some authors. The guidelines for the use of CaD supplementation need not change until well-conducted RCTs that have CV effects as primary outcomes and adjust for major confounders indicate otherwise. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

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.

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

Controlling Response Shift Bias: The Use of the Retrospective Pre-Test Design in the Evaluation of a Master's Programme

ERIC Educational Resources Information Center

Drennan, Jonathan; Hyde, Abbey

2008-01-01

Traditionally the measures used to evaluate the impact of an educational programme on student outcomes and the extent to which students change is a comparison of the student's pre-test scores with his/her post-test scores. However, this method of evaluating change may be problematic due to the confounding factor of response shift bias when student…

Exposure to diesel and gasoline engine emissions and the risk of lung cancer.

PubMed

Parent, Marie-Elise; Rousseau, Marie-Claude; Boffetta, Paolo; Cohen, Aaron; Siemiatycki, Jack

2007-01-01

Pollution from motor vehicles constitutes a major environmental health problem. The present paper describes associations between diesel and gasoline engine emissions and lung cancer, as evidenced in a 1979-1985 population-based case-control study in Montreal, Canada. Cases were 857 male lung cancer patients. Controls were 533 population controls and 1,349 patients with other cancer types. Subjects were interviewed to obtain a detailed lifetime job history and relevant data on potential confounders. Industrial hygienists translated each job description into indices of exposure to several agents, including engine emissions. There was no evidence of excess risks of lung cancer with exposure to gasoline exhaust. For diesel engine emissions, results differed by control group. When cancer controls were considered, there was no excess risk. When population controls were studied, the odds ratios, after adjustments for potential confounders, were 1.2 (95% confidence interval: 0.8, 1.8) for any exposure and 1.6 (95% confidence interval: 0.9, 2.8) for substantial exposure. Confidence intervals between risk estimates derived from the two control groups overlapped considerably. These results provide some limited support for the hypothesis of an excess lung cancer risk due to diesel exhaust but no support for an increase in risk due to gasoline exhaust.

Maternal age at first birth and offspring criminality: Using the children-of-twins design to test causal hypotheses

PubMed Central

Coyne, Claire A; Långström, Niklas; Rickert, Martin E; Lichtenstein, Paul; D’Onofrio, Brian M

2013-01-01

Teenage childbirth is a risk factor for poor offspring outcomes, particularly offspring antisocial behaviour. It is not clear if maternal age at first birth (MAFB) is causally associated with offspring antisocial behavior or if this association is due to selection factors that influence both the likelihood that a young woman gives birth early and that her offspring engage in antisocial behavior. The current study addresses the limitations of previous research by using longitudinal data from Swedish national registries and children-of-siblings and children-of-twins comparisons to identify the extent to which the association between MAFB and offspring criminal convictions is consistent with a causal influence and confounded by genetic or environmental factors that make cousins similar. We found offspring born to mothers who began childbearing earlier were more likely to be convicted of a crime than offspring born to mothers who delayed childbearing. The results from comparisons of differentially exposed cousins, especially born to discordant MZ twin sisters, provide support for a causal association between MAFB and offspring criminal convictions. The analyses also found little evidence for genetic confounding due to passive gene-environment correlation. Future studies are needed to replicate these findings and to identify environmental risk factors that mediate this causal association. PMID:23398750

Impact of Hurricane Exposure on Reproductive Health Outcomes, Florida, 2004.

PubMed

Grabich, Shannon C; Robinson, Whitney R; Konrad, Charles E; Horney, Jennifer A

2017-08-01

Prenatal hurricane exposure may be an increasingly important contributor to poor reproductive health outcomes. In the current literature, mixed associations have been suggested between hurricane exposure and reproductive health outcomes. This may be due, in part, to residual confounding. We assessed the association between hurricane exposure and reproductive health outcomes by using a difference-in-difference analysis technique to control for confounding in a cohort of Florida pregnancies. We implemented a difference-in-difference analysis to evaluate hurricane weather and reproductive health outcomes including low birth weight, fetal death, and birth rate. The study population for analysis included all Florida pregnancies conceived before or during the 2003 and 2004 hurricane season. Reproductive health data were extracted from vital statistics records from the Florida Department of Health. In 2004, 4 hurricanes (Charley, Frances, Ivan, and Jeanne) made landfall in rapid succession; whereas in 2003, no hurricanes made landfall in Florida. Overall models using the difference-in-difference analysis showed no association between exposure to hurricane weather and reproductive health. The inconsistency of the literature on hurricane exposure and reproductive health may be in part due to biases inherent in pre-post or regression-based county-level comparisons. We found no associations between hurricane exposure and reproductive health. (Disaster Med Public Health Preparedness. 2017;11:407-411).

Maternal age at first birth and offspring criminality: using the children of twins design to test causal hypotheses.

PubMed

Coyne, Claire A; Långström, Niklas; Rickert, Martin E; Lichtenstein, Paul; D'Onofrio, Brian M

2013-02-01

Teenage childbirth is a risk factor for poor offspring outcomes, particularly offspring antisocial behavior. It is not clear, however, if maternal age at first birth (MAFB) is causally associated with offspring antisocial behavior or if this association is due to selection factors that influence both the likelihood that a young woman gives birth early and that her offspring engage in antisocial behavior. The current study addresses the limitations of previous research by using longitudinal data from Swedish national registries and children of siblings and children of twins comparisons to identify the extent to which the association between MAFB and offspring criminal convictions is consistent with a causal influence and confounded by genetic or environmental factors that make cousins similar. We found offspring born to mothers who began childbearing earlier were more likely to be convicted of a crime than offspring born to mothers who delayed childbearing. The results from comparisons of differentially exposed cousins, especially born to discordant monozygotic twin sisters, provide support for a causal association between MAFB and offspring criminal convictions. The analyses also found little evidence for genetic confounding due to passive gene-environment correlation. Future studies are needed to replicate these findings and to identify environmental risk factors that mediate this causal association.

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...

Effects of anthropogenic heavy metal contamination on litter decomposition in streams - A meta-analysis.

PubMed

Ferreira, Verónica; Koricheva, Julia; Duarte, Sofia; Niyogi, Dev K; Guérold, François

2016-03-01

Many streams worldwide are affected by heavy metal contamination, mostly due to past and present mining activities. Here we present a meta-analysis of 38 studies (reporting 133 cases) published between 1978 and 2014 that reported the effects of heavy metal contamination on the decomposition of terrestrial litter in running waters. Overall, heavy metal contamination significantly inhibited litter decomposition. The effect was stronger for laboratory than for field studies, likely due to better control of confounding variables in the former, antagonistic interactions between metals and other environmental variables in the latter or differences in metal identity and concentration between studies. For laboratory studies, only copper + zinc mixtures significantly inhibited litter decomposition, while no significant effects were found for silver, aluminum, cadmium or zinc considered individually. For field studies, coal and metal mine drainage strongly inhibited litter decomposition, while drainage from motorways had no significant effects. The effect of coal mine drainage did not depend on drainage pH. Coal mine drainage negatively affected leaf litter decomposition independently of leaf litter identity; no significant effect was found for wood decomposition, but sample size was low. Considering metal mine drainage, arsenic mines had a stronger negative effect on leaf litter decomposition than gold or pyrite mines. Metal mine drainage significantly inhibited leaf litter decomposition driven by both microbes and invertebrates, independently of leaf litter identity; no significant effect was found for microbially driven decomposition, but sample size was low. Overall, mine drainage negatively affects leaf litter decomposition, likely through negative effects on invertebrates. Copyright © 2015 Elsevier Ltd. All rights reserved.

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.

Improving observational study estimates of treatment effects using joint modeling of selection effects and outcomes: the case of AAA repair.

PubMed

O'Malley, A James; Cotterill, Philip; Schermerhorn, Marc L; Landon, Bruce E

2011-12-01

When 2 treatment approaches are available, there are likely to be unmeasured confounders that influence choice of procedure, which complicates estimation of the causal effect of treatment on outcomes using observational data. To estimate the effect of endovascular (endo) versus open surgical (open) repair, including possible modification by institutional volume, on survival after treatment for abdominal aortic aneurysm, accounting for observed and unobserved confounding variables. Observational study of data from the Medicare program using a joint model of treatment selection and survival given treatment to estimate the effects of type of surgery and institutional volume on survival. We studied 61,414 eligible repairs of intact abdominal aortic aneurysms during 2001 to 2004. The outcome, perioperative death, is defined as in-hospital death or death within 30 days of operation. The key predictors are use of endo, transformed endo and open volume, and endo-volume interactions. There is strong evidence of nonrandom selection of treatment with potential confounding variables including institutional volume and procedure date, variables not typically adjusted for in clinical trials. The best fitting model included heterogeneous transformations of endo volume for endo cases and open volume for open cases as predictors. Consistent with our hypothesis, accounting for unmeasured selection reduced the mortality benefit of endo. The effect of endo versus open surgery varies nonlinearly with endo and open volume. Accounting for institutional experience and unmeasured selection enables better decision-making by physicians making treatment referrals, investigators evaluating treatments, and policy makers.

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.

Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects.

PubMed

Shaul, Chanan; Blotnick, Simcha; Muszkat, Mordechai; Bialer, Meir; Caraco, Yoseph

2017-02-01

Genetic polymorphisms in CYP2C9 account for 10-20% of the variability in warfarin dose requirement. As such CYP2C9 genetic polymorphisms are commonly included in algorithms aimed to optimize warfarin therapy as a way to account for variability in warfarin responsiveness that is due to altered pharmacokinetics. However, most of the currently available pharmacokinetic data were derived from studies among patients on chronic warfarin therapy and therefore suffer from the confounding effects of disease states and drug interactions. The purpose of the present study was to provide an accurate quantitative estimate of S-warfarin oral clearance (CL S ) among healthy subjects carrying different CYP2C9 genotypes. Single dose of warfarin was administered to 150 non-smokers, age (mean ± SD) 23.3 ± 4.5 years, 60% male, non-obese, healthy subjects. Blood samples were taken for up to 168 h and urine was collected over the entire study period. Compared with carriers of the wild-type CYP2C9*1/*1 genotype (n = 69), CL S was reduced by 25, 39 and 47% among heterozygote for CYP2C9*2 (n = 41) CYP2C9*3 (n = 26) and carriers of 2 variant alleles (n = 14), respectively (p < 0.001). The corresponding decrease in the formation clearance of 6 and 7 S-hydroxy-warfarin was 45, 65 and 75%, respectively (p < 0.001). The current study provides an estimate concerning the effect of CYP2C9 polymorphisms on S-warfarin pharmacokinetics among healthy subjects. As such it is free of the confounding effects of disease states and drug interactions. Further research is needed to evaluate whether the incorporation of quantitative data obtained in the present study into pharmacogenetic warfarin algorithm may enhance its precision. Clinicaltrials.gov Identifier NCT00162474.

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.

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.

Electronic magnification and perceived contrast of video

PubMed Central

Haun, Andrew; Woods, Russell L; Peli, Eli

2012-01-01

Electronic magnification of an image results in a decrease in its perceived contrast. The decrease in perceived contrast could be due to a perceived blur or to limited sampling of the range of contrasts in the original image. We measured the effect on perceived contrast of magnification in two contexts: either a small video was enlarged to fill a larger area, or a portion of a larger video was enlarged to fill the same area as the original. Subjects attenuated the source video contrast to match the perceived contrast of the magnified videos, with the effect increasing with magnification and decreasing with viewing distance. These effects are consistent with expectations based on both the contrast statistics of natural images and the contrast sensitivity of the human visual system. We demonstrate that local regions within videos usually have lower physical contrast than the whole, and that this difference accounts for a minor part of the perceived differences. Instead, visibility of ‘missing content’ (blur) in a video is misinterpreted as a decrease in contrast. We detail how the effects of magnification on perceived contrast can be measured while avoiding confounding factors. PMID:23483111

The association between paracetamol use and asthma: causation or coincidence?

PubMed

Weatherall, M; Ioannides, S; Braithwaite, I; Beasley, R

2015-01-01

A better understanding of the causation of asthma and allergic disorders could potentially lead to intervention strategies that reduce their prevalence and severity. One potential causative factor is the use of paracetamol. Most of the evidence for the link with asthma is from non-experimental studies of paracetamol exposure in utero, infancy, childhood and adult life; however, it has been difficult to rule out confounding and bias in the associations observed. The two randomized clinical trials of the effect of paracetamol in patients with asthma have been difficult to interpret, due to methodological issues. There have been no randomized controlled trials of paracetamol use and the development of asthma. Both asthma and paracetamol use are common, and so even if there is a relatively small effect of paracetamol exposure on the development of asthma or its severity, then such an effect would be of major public health significance. It is proposed that randomized controlled trials of the effect of paracetamol on the development of asthma and its severity are a high research priority. © 2014 John Wiley & Sons Ltd.

An hourly variation in zoo visitor interest: measurement and significance for animal welfare research.

PubMed

Davey, Gareth

2006-01-01

A methodological difficulty facing welfare research on nonhuman animals in the zoo is the large number of uncontrolled variables due to variation within and between study sites. Zoo visitors act as uncontrolled variables, with number, density, size, and behavior constantly changing. This is worrisome because previous research linked visitor variables to animal behavioral changes indicative of stress. There are implications for research design: Studies not accounting for visitors' effect on animal welfare risk confounding (visitor) variables distorting their findings. Zoos need methods to measure and minimize effects of visitor behavior and to ensure that there are no hidden variables in research models. This article identifies a previously unreported variable--hourly variation (decrease) in visitor interest--that may impinge on animal welfare and validates a methodology for measuring it. That visitor interest wanes across the course of the day has important implications for animal welfare management; visitor effects on animal welfare are likely to occur, or intensify, during the morning or in earlier visits when visitor interest is greatest. This article discusses this issue and possible solutions to reduce visitor effects on animal well-being.

Pollution and respiratory disease: can diet or supplements help? A review.

PubMed

Whyand, T; Hurst, J R; Beckles, M; Caplin, M E

2018-05-02

Pollution is known to cause and exacerbate a number of chronic respiratory diseases. The World Health Organisation has placed air pollution as the world's largest environmental health risk factor. There has been recent publicity about the role for diet and anti-oxidants in mitigating the effects of pollution, and this review assesses the evidence for alterations in diet, including vitamin supplementation in abrogating the effects of pollution on asthma and other chronic respiratory diseases. We found evidence to suggest that carotenoids, vitamin D and vitamin E help protect against pollution damage which can trigger asthma, COPD and lung cancer initiation. Vitamin C, curcumin, choline and omega-3 fatty acids may also play a role. The Mediterranean diet appears to be of benefit in patients with airways disease and there appears to be a beneficial effect in smokers however there is no direct evidence regarding protecting against air pollution. More studies investigating the effects of nutrition on rapidly rising air pollution are urgently required. However it is very difficult to design such studies due to the confounding factors of diet, obesity, co-morbid illness, medication and environmental exposure.

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.

Implantable biosensors: analysis of fluorescent light propagation through skin

NASA Astrophysics Data System (ADS)

O'Neal, D. P.; McShane, Michael J.; Pishko, Michael V.; Cote, Gerard L.

2001-06-01

Progress towards a painless and hygienic glucose monitoring procedure for diabetics continues as the growth of diabetes mellitus reaches epidemic proportions in the American population. Utilizing an implantable fluorescence based glucose assay, the minimally invasive approach presented here has previously shown promise towards this goal in terms of glucose specificity and quantification for in vitro environments. However, in realistic physiological circumstances the depth of the implant can vary and optical properties of skin can change due to normal physiological conditions. Additionally, naturally occurring auto-fluorescence can obscure the sensor signal. An important concern under these conditions is that variations of fluorescent intensity due to these or other causes might be mistaken for glucose concentration fluctuations. New data shows that fluorescence-based glucose assays can be probed and interpreted in terms of glucose concentrations through pig skin at depths of up to 700 mm when immobilized in a bio-compatible polymer. When a combination of two fluorophores are employed as demonstrated here, reasonable changes in skin thickness and the confounding effects of the variations inherent in skin can be overcome for this glucose sensing application.

Illusion of control: the role of personal involvement.

PubMed

Yarritu, Ion; Matute, Helena; Vadillo, Miguel A

2014-01-01

The illusion of control consists of overestimating the influence that our behavior exerts over uncontrollable outcomes. Available evidence suggests that an important factor in development of this illusion is the personal involvement of participants who are trying to obtain the outcome. The dominant view assumes that this is due to social motivations and self-esteem protection. We propose that this may be due to a bias in contingency detection which occurs when the probability of the action (i.e., of the potential cause) is high. Indeed, personal involvement might have been often confounded with the probability of acting, as participants who are more involved tend to act more frequently than those for whom the outcome is irrelevant and therefore become mere observers. We tested these two variables separately. In two experiments, the outcome was always uncontrollable and we used a yoked design in which the participants of one condition were actively involved in obtaining it and the participants in the other condition observed the adventitious cause-effect pairs. The results support the latter approach: Those acting more often to obtain the outcome developed stronger illusions, and so did their yoked counterparts.

Energetics and longevity in birds

PubMed Central

Furness, L. J.

2008-01-01

The links between energy expenditure and ageing are different at different levels of enquiry. When studies have examined the relationships between different species within a given class the association is generally negative—animals with greater metabolism per gram of tissue live shorter lives. Within species, or between classes (e.g. between birds and mammals) the association is the opposite—animals with higher metabolic rates live longer. We have previously shown in mammals that the negative association between lifespan and metabolic rate is in fact an artefact of using resting rather than daily energy expenditure, and of failing to adequately take into account the confounding effects of body size and the lack of phylogenetic independence of species data. When these factors are accounted for, across species of mammals, the ones with higher metabolism also have the largest lifetime expenditures of energy—consistent with the inter-class and intra-specific data. A previous analysis in birds did not yield the same pattern, but this may have been due to a lack of sufficient power in the analysis. Here we present an analysis of a much enlarged data set (>300 species) for metabolic and longevity traits in birds. These data show very similar patterns to those in mammals. Larger individuals have longer lives and lower per-gram resting and daily energy expenditures, hence there is a strong negative relationship between longevity and mass-specific metabolism. This relationship disappears when the confounding effects of body mass and phylogeny are accounted for. Across species of birds, lifetime expenditure of energy per gram of tissue based on both daily and resting energy expenditure is positively related to metabolic intensity, mirroring these statistical relationships in mammals and synergising with the positive associations of metabolism with lifespan within species and between vertebrate classes. PMID:19424858

Investigating the possible causal role of coffee consumption with prostate cancer risk and progression using Mendelian randomization analysis

PubMed Central

Martin, Richard M.; Geybels, Milan S.; Stanford, Janet L.; Shui, Irene; Eeles, Rosalind; Easton, Doug; Kote‐Jarai, Zsofia; Amin Al Olama, Ali; Benlloch, Sara; Muir, Kenneth; Giles, Graham G; Wiklund, Fredrik; Gronberg, Henrik; Haiman, Christopher A; Schleutker, Johanna; Nordestgaard, Børge G.; Travis, Ruth C; Neal, David; Pashayan, Nora; Khaw, Kay‐Tee; Blot, William; Thibodeau, Stephen; Maier, Christiane; Kibel, Adam S; Cybulski, Cezary; Cannon‐Albright, Lisa; Brenner, Hermann; Park, Jong; Kaneva, Radka; Batra, Jyotsna; Teixeira, Manuel R; Pandha, Hardev; Donovan, Jenny; Munafò, Marcus R.

2016-01-01

Coffee consumption has been shown in some studies to be associated with lower risk of prostate cancer. However, it is unclear if this association is causal or due to confounding or reverse causality. We conducted a Mendelian randomisation analysis to investigate the causal effects of coffee consumption on prostate cancer risk and progression. We used two genetic variants robustly associated with caffeine intake (rs4410790 and rs2472297) as proxies for coffee consumption in a sample of 46,687 men of European ancestry from 25 studies in the PRACTICAL consortium. Associations between genetic variants and prostate cancer case status, stage and grade were assessed by logistic regression and with all‐cause and prostate cancer‐specific mortality using Cox proportional hazards regression. There was no clear evidence that a genetic risk score combining rs4410790 and rs2472297 was associated with prostate cancer risk (OR per additional coffee increasing allele: 1.01, 95% CI: 0.98,1.03) or having high‐grade compared to low‐grade disease (OR: 1.01, 95% CI: 0.97,1.04). There was some evidence that the genetic risk score was associated with higher odds of having nonlocalised compared to localised stage disease (OR: 1.03, 95% CI: 1.01, 1.06). Amongst men with prostate cancer, there was no clear association between the genetic risk score and all‐cause mortality (HR: 1.00, 95% CI: 0.97,1.04) or prostate cancer‐specific mortality (HR: 1.03, 95% CI: 0.98,1.08). These results, which should have less bias from confounding than observational estimates, are not consistent with a substantial effect of coffee consumption on reducing prostate cancer incidence or progression. PMID:27741566

Using Claims Data to Predict Dependency in Activities of Daily Living as a Proxy for Frailty

PubMed Central

Faurot, Keturah R.; Funk, Michele Jonsson; Pate, Virginia; Brookhart, M. Alan; Patrick, Amanda; Hanson, Laura C.; Castillo, Wendy Camelo; Stürmer, Til

2014-01-01

Purpose Estimating drug effectiveness and safety among older adults in population-based studies using administrative healthcare claims can be hampered by unmeasured confounding due to frailty. A claims-based algorithm that identifies patients likely to be dependent, a proxy for frailty, may improve confounding control. Our objective was to develop an algorithm to predict dependency in activities of daily living (ADL) in a sample of Medicare beneficiaries. Methods Community-dwelling respondents to the 2006 Medicare Current Beneficiary Survey, >65 years old, with Medicare Part A, B, home health, and hospice claims were included. ADL dependency was defined as needing help with bathing, eating, walking, dressing, toileting, or transferring. Potential predictors were demographics, ICD-9 diagnosis/procedure and durable medical equipment codes for frailty-associated conditions. Multivariable logistic regression was to predict ADL dependency. Cox models estimated hazard ratios for death as a function of observed and predicted ADL dependency. Results Of 6391 respondents, 57% were female, 88% white, and 38% were ≥80. The prevalence of ADL dependency was 9.5%. Strong predictors of ADL dependency were charges for a home hospital bed (OR=5.44, 95% CI=3.28–9.03) and wheelchair (OR=3.91, 95% CI=2.78–5.51). The c-statistic of the final model was 0.845. Model-predicted ADL dependency of 20% or greater was associated with a hazard ratio for death of 3.19 (95% CI: 2.78, 3.68). Conclusions An algorithm for predicting ADL dependency using healthcare claims was developed to measure some aspects of frailty. Accounting for variation in frailty among older adults could lead to more valid conclusions about treatment use, safety, and effectiveness. PMID:25335470

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.

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.

Heterogeneous binary interactions of taste primaries: perceptual outcomes, physiology, and future directions.

PubMed

Wilkie, Lynn M; Capaldi Phillips, Elizabeth D

2014-11-01

Complex taste experiences arise from the combinations of five taste primaries. Here we review the literature on binary interactions of heterogeneous taste primaries, focusing on perceptual results of administering mixtures of aqueous solutions to human participants. Some interactions proved relatively consistent across tastants and experimental methods: sour acids enhanced saltiness, salts and sweeteners suppressed bitterness, sweeteners suppressed sourness, and sour acids enhanced bitterness. However, for the majority of interactions there were differential effects based on the tastants and their concentrations. Drawing conclusions about interactions with umami is currently not possible due to the low number of primary source studies investigating it and the confounding sodium ions in monosodium glutamate (MSG). Speculative physiological explanations are provided that fit the current data and suggestions for future research studies are proposed. Copyright © 2014 Elsevier Ltd. All rights reserved.

Critical assessment of opposing views on trends in childhood cancer.

PubMed

Bukowski, J A

2000-01-01

Two articles reaching opposite conclusions on the current trends in childhood cancer have recently appeared in the literature. One concluded that pediatric cancers have increased dramatically, suggesting an effect from environmental hazards; the other concluded that rates for the major pediatric cancers have remained fairly stable, except for modest increases due to improvements in diagnosis or reporting. This review discusses the reasons for this discrepancy, including differences in the populations, age groups, and time periods analyzed. The arguments in favor of an increase are examined and shown to provide no convincing evidence that environmental pollutants have increased pediatric cancer rates over the past 20 to 30 years. Any suggested increase appears to be the result of non-causal factors, such as selective analysis and reporting, residual confounding by age, random variation, and stepwise improvements in diagnosis and classification.

Explicit processing demands reveal language modality-specific organization of working memory.

PubMed

Rudner, Mary; Rönnberg, Jerker

2008-01-01

The working memory model for Ease of Language Understanding (ELU) predicts that processing differences between language modalities emerge when cognitive demands are explicit. This prediction was tested in three working memory experiments with participants who were Deaf Signers (DS), Hearing Signers (HS), or Hearing Nonsigners (HN). Easily nameable pictures were used as stimuli to avoid confounds relating to sensory modality. Performance was largely similar for DS, HS, and HN, suggesting that previously identified intermodal differences may be due to differences in retention of sensory information. When explicit processing demands were high, differences emerged between DS and HN, suggesting that although working memory storage in both groups is sensitive to temporal organization, retrieval is not sensitive to temporal organization in DS. A general effect of semantic similarity was also found. These findings are discussed in relation to the ELU model.

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.

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.

The association between childhood obesity and tooth eruption.

PubMed

Must, Aviva; Phillips, Sarah M; Tybor, David J; Lividini, Keith; Hayes, Catherine

2012-10-01

Obesity is a growth-promoting process as evidenced by its effect on the timing of puberty. Although studies are limited, obesity has been shown to affect the timing of tooth eruption. Both the timing and sequence of tooth eruption are important to overall oral health. The purpose of this study was to examine the association between obesity and tooth eruption. Data were combined from three consecutive cycles (2001-2006) of the National Health and Nutrition Examination Survey (NHANES) and analyzed to examine associations between the number of teeth erupted (NET) and obesity status (BMI z-score >95th percentile BMI relative to the Centers for Disease Control and Prevention (CDC) growth reference) among children 5 up to 14 years of age, controlling for potential confounding by age, gender, race, and socioeconomic status (SES). Obesity is significantly associated with having a higher average NET during the mixed dentition period. On average, teeth of obese children erupted earlier than nonobese children with obese children having on average 1.44 more teeth erupted than nonobese children, after adjusting for age, gender, and race/ethnicity (P < 0.0001). SES was not a confounder of the observed associations. Obese children, on average, have significantly more teeth erupted than nonobese children after adjusting for gender, age, and race. These findings may have clinical importance in the area of dental and orthodontic medicine both in terms of risk for dental caries due to extended length of time exposed in the oral cavity and sequencing which may increase the likelihood of malocclusions.

Unemployment Is a Risk Factor for Hospitalization Due to Alcohol Problems: A Longitudinal Study Based on the Stockholm Public Health Cohort (SPHC).

PubMed

Backhans, Mona Christina; Balliu, Natalja; Lundin, Andreas; Hemmingsson, Tomas

2016-11-01

This study examined the associations between unemployment and alcohol-related hospitalization or mortality and to what extent these associations may be confounded by alcohol consumption and alcohol problems before unemployment. The study was based on the Stockholm Public Health Cohort (SPHC), a population-based stratified random sample with a baseline questionnaire in 2002/2003 and record linkages up to year 2011. The final sample in the study consists of 15,841 people aged 18-60 years. Unemployment was defined as any registration at the public employment services during 2003-2005. The outcome was alcohol-related hospitalization and alcohol-related mortality during 2006-2011. Confounders were age, sex, and education, and we further adjusted for baseline alcohol consumption and alcohol-related hospitalization before the study period. Cox proportional hazard models were fit, and associations were expressed as hazard ratios (HRs). In the fully adjusted model, unemployment was associated with an increased risk of alcohol-related hospitalization or mortality, with a more than threefold hazard (HR = 3.38, 95% CI [1.81, 6.31]) compared with no unemployment during the exposure period. There was a moderate attenuating effect of prior alcohol consumption and alcohol-related hospitalization. Any unemployment in 2003-2005 was highly related to having experienced an alcohol-related diagnosis during the 6-year follow-up, even after controlling for risky use of alcohol and prior hospitalization.

Effects of Storage-Aged RBC Transfusions on Endothelial Function in Hospitalized Patients

PubMed Central

Neuman, Robert; Hayek, Salim; Rahman, Ayaz; Poole, Joseph C.; Menon, Vivek; Sher, Salman; Newman, James L.; Karatela, Sulaiman; Polhemus, David; Lefer, David J.; De Staercke, Christine; Hooper, Craig; Quyyumi, Arshed A.; Roback, John D.

2014-01-01

Background Clinical and animal studies indicate that transfusions of older stored RBCs impair clinical outcomes as compared to fresh RBC transfusions. It has been suggested that this effect is due to inhibition of NO-mediated vasodilation following transfusion of older RBC units. However, to date this effect has not been identified in human transfusion recipients. Study Design and Methods Forty-three hospitalized patients with transfusion orders were randomized to receive either fresh (< 14 days) or older stored (> 21 days) RBC units. Prior to transfusion, and at selected time points after the start of transfusion, endothelial function was assessed using non-invasive flow-mediated dilation assays. Results Following transfusion of older RBC units, there was a significant reduction in NO-mediated vasodilation at 24 hours after transfusion (p=0.045), while fresh RBC transfusions had no effect (p=0.231). Conclusions The present study suggests for the first time a significant inhibitory effect of transfused RBC units stored > 21 days on NO-mediated vasodilation in anemic hospitalized patients. This finding lends further support to the hypothesis that deranged NO signaling mediates adverse clinical effects of older RBC transfusions. Future investigations will be necessary to address possible confounding factors and confirm these results. PMID:25393772

Birth order, family size, and children's use of physician services.

PubMed Central

Tessler, R

1980-01-01

The purpose of this study is to separate out the effects of number of siblings and birth order on children's use of physician services. Prior research has consistently revealed an inverse relationship between family size and physician visits, but the possible confounding influence of the child's ordinal position in the family has been ignored. Later born children may be taken to the doctor less often than first and other early borns because of their parents' increasing knowledgeability in regard to child care as well as their growing understanding of the uses and limitations of physician visits. On the assumption that part of the family size effect observed in prior research may have been due to the clustering of first and early borns in small families, an inverse relationship between birth order and physician utilization is hypothesized. Support for this hypothesis comes from an empirical study of 1,665 children from 587 families in which variation in family size is statistically controlled. PMID:7372499

Optimized design and analysis of preclinical intervention studies in vivo

PubMed Central

Laajala, Teemu D.; Jumppanen, Mikael; Huhtaniemi, Riikka; Fey, Vidal; Kaur, Amanpreet; Knuuttila, Matias; Aho, Eija; Oksala, Riikka; Westermarck, Jukka; Mäkelä, Sari; Poutanen, Matti; Aittokallio, Tero

2016-01-01

Recent reports have called into question the reproducibility, validity and translatability of the preclinical animal studies due to limitations in their experimental design and statistical analysis. To this end, we implemented a matching-based modelling approach for optimal intervention group allocation, randomization and power calculations, which takes full account of the complex animal characteristics at baseline prior to interventions. In prostate cancer xenograft studies, the method effectively normalized the confounding baseline variability, and resulted in animal allocations which were supported by RNA-seq profiling of the individual tumours. The matching information increased the statistical power to detect true treatment effects at smaller sample sizes in two castration-resistant prostate cancer models, thereby leading to saving of both animal lives and research costs. The novel modelling approach and its open-source and web-based software implementations enable the researchers to conduct adequately-powered and fully-blinded preclinical intervention studies, with the aim to accelerate the discovery of new therapeutic interventions. PMID:27480578

Optimized design and analysis of preclinical intervention studies in vivo.

PubMed

Laajala, Teemu D; Jumppanen, Mikael; Huhtaniemi, Riikka; Fey, Vidal; Kaur, Amanpreet; Knuuttila, Matias; Aho, Eija; Oksala, Riikka; Westermarck, Jukka; Mäkelä, Sari; Poutanen, Matti; Aittokallio, Tero

2016-08-02

Recent reports have called into question the reproducibility, validity and translatability of the preclinical animal studies due to limitations in their experimental design and statistical analysis. To this end, we implemented a matching-based modelling approach for optimal intervention group allocation, randomization and power calculations, which takes full account of the complex animal characteristics at baseline prior to interventions. In prostate cancer xenograft studies, the method effectively normalized the confounding baseline variability, and resulted in animal allocations which were supported by RNA-seq profiling of the individual tumours. The matching information increased the statistical power to detect true treatment effects at smaller sample sizes in two castration-resistant prostate cancer models, thereby leading to saving of both animal lives and research costs. The novel modelling approach and its open-source and web-based software implementations enable the researchers to conduct adequately-powered and fully-blinded preclinical intervention studies, with the aim to accelerate the discovery of new therapeutic interventions.

Diversity of gastrointestinal helminths in Dall's sheep and the negative association of the abomasal nematode, Marshallagia marshalli, with fitness indicators

PubMed Central

Ruckstuhl, Kathreen; Hoberg, Eric P.; Veitch, Alasdair; Kutz, Susan J.

2018-01-01

Gastrointestinal helminths can have a detrimental effect on the fitness of wild ungulates. Arctic and Subarctic ecosystems are ideal for the study of host-parasite interactions due to the comparatively simple ecological interactions and limited confounding factors. We used a unique dataset assembled in the early seventies to study the diversity of gastrointestinal helminths and their effect on fitness indicators of Dall’s sheep, Ovis dalli dalli, in the Mackenzie Mountains, Northwest Territories, Canada. Parasite diversity included nine species, among which the abomasal nematode Marshallagia marshalli occurred with the highest prevalence and infection intensity. The intensity of M. marshalli increased with age and was negatively associated with body condition and pregnancy status in Dall’s sheep across all the analyses performed. The intensity of the intestinal whipworm, Trichuris schumakovitschi, decreased with age. No other parasites were significantly associated with age, body condition, or pregnancy. Our study suggests that M. marshalli might negatively influence fitness of adult female Dall’s sheep. PMID:29538393

Of toothy grins and angry snarls--open mouth displays contribute to efficiency gains in search for emotional faces.

PubMed

Horstmann, Gernot; Lipp, Ottmar V; Becker, Stefanie I

2012-05-25

The emotional face-in-a-crowd effect is widely cited, but its origin remains controversial, particularly with photorealistic stimuli. Recently, it has been suggested that one factor underlying the guidance of attention by a photorealistic emotional face in visual search might be the visibility of teeth, a hypothesis, however, that has not been studied systematically to date. The present experiments manipulate the visibility of teeth experimentally and orthogonally to facial emotion. Results suggest that much of the face-in-a-crowd effect with photorealistic emotional faces is due to visible teeth, and that the visibility of teeth can create a search advantage for either a happy or an angry target face when teeth visibility and facial emotion are confounded. Further analyses clarify that the teeth visibility primarily affects the speed with which neutral crowds are scanned, shedding new light on the mechanism that evokes differences in search efficiency for different emotional expressions.

Diversity of gastrointestinal helminths in Dall's sheep and the negative association of the abomasal nematode, Marshallagia marshalli, with fitness indicators.

PubMed

Aleuy, O Alejadro; Ruckstuhl, Kathreen; Hoberg, Eric P; Veitch, Alasdair; Simmons, Norman; Kutz, Susan J

2018-01-01

Gastrointestinal helminths can have a detrimental effect on the fitness of wild ungulates. Arctic and Subarctic ecosystems are ideal for the study of host-parasite interactions due to the comparatively simple ecological interactions and limited confounding factors. We used a unique dataset assembled in the early seventies to study the diversity of gastrointestinal helminths and their effect on fitness indicators of Dall's sheep, Ovis dalli dalli, in the Mackenzie Mountains, Northwest Territories, Canada. Parasite diversity included nine species, among which the abomasal nematode Marshallagia marshalli occurred with the highest prevalence and infection intensity. The intensity of M. marshalli increased with age and was negatively associated with body condition and pregnancy status in Dall's sheep across all the analyses performed. The intensity of the intestinal whipworm, Trichuris schumakovitschi, decreased with age. No other parasites were significantly associated with age, body condition, or pregnancy. Our study suggests that M. marshalli might negatively influence fitness of adult female Dall's sheep.

No effect of a parasite on reproduction in stickleback males: a laboratory artefact?

PubMed

Candolin, U; Voigt, H R

2001-04-01

Experiments are often carried out in the laboratory under artificial conditions. Although this can control for confounding factors, it may eliminate important factors that under natural conditions mediate the interaction under investigation. Here, we show that different results can be gained in the field and in the laboratory regarding host-parasite interaction. In the field, courting three-spined stickleback males, Gasterosteus aculeatus, were less often infected with plerocercoids of a cestode tapeworm, Schistocephalus solidus, than shoaling males. However, when a random sample of males was allowed to nest and court females in individual aquaria in the laboratory, both uninfected and infected males built nests and courted females. Moreover, while the few infected males that courted females in the field expressed less red nuptial coloration than uninfected courting males, there was no difference in redness between infected and uninfected males in the laboratory. We argue that the different results gained in the field and in the laboratory are due to differences in the cost of reproduction, due to differences in the resource pool of the males. The favourable conditions in the laboratory exclude factors such as predation risk, social interactions, and fluctuating environmental conditions that may use up resources in the field and mediate the effect of the parasite.

Associations between workplace factors and carpal tunnel syndrome: A multi-site cross sectional study.

PubMed

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

2015-05-01

Few large epidemiologic studies have used rigorous case criteria, individual-level exposure measurements, and appropriate control for confounders to examine associations between workplace psychosocial and biomechanical factors and carpal tunnel syndrome (CTS). Pooling data from five independent research studies, we assessed associations between prevalent CTS and personal, work psychosocial, and biomechanical factors while adjusting for confounders using multivariable logistic regression. Prevalent CTS was associated with personal factors of older age, obesity, female sex, medical conditions, previous distal upper extremity disorders, workplace measures of peak forceful hand activity, a composite measure of force and repetition (ACGIH Threshold Limit Value for Hand Activity Level), and hand vibration. In this cross-sectional analysis of production and service workers, CTS prevalence was associated with workplace and biomechanical factors. The findings were similar to those from a prospective analysis of the same cohort with differences that may be due to recall bias and other factors. © 2015 Wiley Periodicals, Inc.

Incidence of workers compensation indemnity claims across socio-demographic and job characteristics.

PubMed

Du, Juan; Leigh, J Paul

2011-10-01

We hypothesized that low socioeconomic status, employer-provided health insurance, low wages, and overtime were predictors of reporting workers compensation indemnity claims. We also tested for gender and race disparities. Responses from 17,190 (person-years) Americans participating in the Panel Study of Income Dynamics, 1997-2005, were analyzed with logistic regressions. The dependent variable indicated whether the subject collected benefits from a claim. Odds ratios for men and African-Americans were relatively large and strongly significant predictors of claims; significance for Hispanics was moderate and confounded by education. Odds ratios for variables measuring education were the largest for all statistically significant covariates. Neither low wages nor employer-provided health insurance was a consistent predictor. Due to confounding from the "not salaried" variable, overtime was not a consistently significant predictor. Few studies use nationally representative longitudinal data to consider which demographic and job characteristics predict reporting workers compensation indemnity cases. This study did and tested some common hypotheses about predictors. Copyright © 2011 Wiley-Liss, Inc.

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.

Education and smoking: confounding or effect modification by phenotypic personality traits?

PubMed

Chapman, Benjamin; Fiscella, Kevin; Duberstein, Paul; Kawachi, Ichiro

2009-12-01

Little is known about whether educational gradients in smoking patterns can be explained by financial measures of socioeconomic status (SES) and/or personality traits. To assess whether the relationship of education to (1) never smoking and (2) having quit smoking would be confounded by financial measures of SES or by personality; whether lower Neuroticism and higher Conscientiousness would be associated with having abstained from or quit smoking; and whether education effects were modified by personality. Using data from the Midlife Development in the US National Survey, 2,429 individuals were classified as current (n = 695), former (n = 999), or never (n = 735) smokers. Multinomial logistic regressions examined study questions. Greater education was strongly associated with both never and former smoking, with no confounding by financial status and personality. Never smoking was associated with lower Openness and higher Conscientiousness, while have quit was associated with higher Neuroticism. Education interacted additively with Conscientiousness to increase and with Openness to decrease the probability of never smoking. Education and personality should be considered unconfounded smoking risks in epidemiologic and clinical studies. Educational associations with smoking may vary by personality dispositions, and prevention and intervention programs should consider both sets of factors.

Bed-sharing and risk of hospitalisation due to pneumonia and diarrhoea in infancy: the 2004 Pelotas Birth Cohort

PubMed Central

Ngale, Kátia M A; Santos, Iná S; González-Chica, David A; de Barros, Aluísio J D; Matijasevich, Alicia

2013-01-01

Objective To investigate the association between bed-sharing with the mother at 3 months of age and incidence of hospitalisation due to pneumonia and diarrhoea between 3 and 12 months. Methods The 2004 Pelotas Birth Cohort included all live births to mothers living in Pelotas, Brazil, in 2004. Information on bed-sharing was obtained at the 3-month follow-up visit, and on hospitalisations at the 12-month visit, both based on mothers’ reports. Only singleton infants with complete information on hospitalisation were analysed. Results 3906 infants were included. The bed-sharing prevalence at 3 months was 46.4% (95% CI 44.9 to 48.0%). The incidence of pneumonia admissions between 3 and 12 months was 3.6% (95% CI 3.3 to 4.2%) and diarrhoea, 0.9% (95% CI 0.6 to 1.2%). In crude analyses, bed-sharing with the mother was associated with higher incidence of hospitalisation due to both pneumonia and diarrhoea. There was interaction between bed-sharing and duration of breastfeeding regarding the chance of admission due to pneumonia. Among infants breastfed for 3 months or less, the chance of hospitalisation due to pneumonia among bed-sharers was almost twice as high as among non-bed-sharers (adjusted OR 1.96; 95% CI 1.08 to 3.55). There was no association between bed-sharing and hospitalisation due to pneumonia among infants breastfed for longer than 3 months in crude or adjusted analyses. The association between bed-sharing and admissions due to diarrhoea lost statistical significance after allowing for confounders. Conclusions The effect of bed-sharing in infancy on the risk of hospitalisation due to pneumonia depends on breastfeeding, such that weaned children present higher risk. PMID:23100381

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.

Cancer deaths and occupational exposure in a group of plutonium workers.

PubMed

Fallahian, Naz Afarin; Brey, Richard R; Tivis, Rick D; Piland, Neill F; Simpson, David R

2012-04-01

An exploratory epidemiological study was conducted for 319 deceased nuclear workers who had intakes of transuranic radionuclides and histories of employment during the time period from 1943 to 1995. The workers were employed at various facilities throughout the United States, including the Department of Energy defense facilities and uranium mining and milling sites. The majority of individuals were involved in documented radiological incidents during their careers. All had voluntarily agreed to donate their organs or whole body to the United States Transuranium and Uranium Registries. External and internal dose assessments were performed using occupational exposure histories and postmortem concentrations of transuranic radionuclides in critical organs. Statistical data analyses were performed to investigate the potential relationship between radiation exposure and causes of death within this population due to cancers of the lungs, liver, and all sites combined while controlling for the effects of other confounders. No association was found between radiation exposure and death due to cancer (α = 0.05). However, statistically significant associations were found between death due to any type of cancer and smoking (yes or no) (odds ratio = 5.41; 95% CI: 1.42 to 20.67) and rate of cigarette smoking (packs per day) (odds ratio = 2.70; 95% CI: 1.37 to 5.30).

Mapping eQTL Networks with Mixed Graphical Markov Models

PubMed Central

Tur, Inma; Roverato, Alberto; Castelo, Robert

2014-01-01

Expression quantitative trait loci (eQTL) mapping constitutes a challenging problem due to, among other reasons, the high-dimensional multivariate nature of gene-expression traits. Next to the expression heterogeneity produced by confounding factors and other sources of unwanted variation, indirect effects spread throughout genes as a result of genetic, molecular, and environmental perturbations. From a multivariate perspective one would like to adjust for the effect of all of these factors to end up with a network of direct associations connecting the path from genotype to phenotype. In this article we approach this challenge with mixed graphical Markov models, higher-order conditional independences, and q-order correlation graphs. These models show that additive genetic effects propagate through the network as function of gene–gene correlations. Our estimation of the eQTL network underlying a well-studied yeast data set leads to a sparse structure with more direct genetic and regulatory associations that enable a straightforward comparison of the genetic control of gene expression across chromosomes. Interestingly, it also reveals that eQTLs explain most of the expression variability of network hub genes. PMID:25271303

Technology transfer through performance management: the effects of graphical feedback and positive reinforcement on drug treatment counselors' behavior.

PubMed

Andrzejewski, M E; Kirby, K C; Morral, A R; Iguchi, M Y

2001-07-01

After drug treatment counselors at a community-based methadone treatment clinic were trained in implementing a contingency management (CM) intervention, baseline measures of performance revealed that, on average, counselors were meeting the performance criteria specified by the treatment protocol about 42% of the time. Counselors were exposed to graphical feedback and a drawing for cash prizes in an additive within-subjects design to assess the effectiveness of these interventions in improving protocol adherence. Counselor performance measures increased to 71% during the graphical feedback condition, and to 81% during the drawing. Each counselor's performance improved during the intervention conditions. Additional analyses suggested that counselors did not have skill deficits that hindered implementation. Rather, protocol implementation occurred more frequently when consequences were added, thereby increasing the overall proportion of criteria met. Generalizations, however, may be limited due to a small sample size and possible confounding of time and intervention effects. Nonetheless, present results show promise that feedback and positive reinforcement could be used to improve technology transfer of behavioral interventions into community clinic settings.

Understanding Cataract Risk in Aerospace Flight Crew And Review of Mechanisms of Cataract Formation

NASA Technical Reports Server (NTRS)

Jones, Jeffrey A.; McCarten, M.; Manuel, K.; Djojonegoro, B.; Murray, J.; Cucinotta, F.; Feiversen, A.; Wear, M.

2006-01-01

Induction of cataracts by occupational exposure in flight crew has been an important topic of interest in aerospace medicine in the past five years, in association with numerous reports of flight-associated disease incidences. Due to numerous confounding variables, it has been difficult to determine if there is increased cataract risk directly caused by interaction with the flight environment, specifically associated with added radiation exposure during flight. Military aviator records from the United States Air Force (USAF) and Navy (USN) and US astronauts at the National Aeronautics and Space Administration (NASA)/Lyndon B. Johnson Space Center (JSC) were evaluated for the presence, location and age of diagnosis of cataracts. Military aviators were found to have a statistically significant younger average age of onset of their cataracts compared with astronauts, however the incidence density of cataracts was found to be statistically higher in astronauts than in military aviators. USAF and USN aviator s cataracts were most commonly located in the posterior subcapsular region of the lens while astronauts cataracts were most likely to originate generally in the cortical zone. A prospective clinical trial which controls for confounding variables in examination technique, cataract classification, diet, exposure, and pharmacological intervention is needed to determine what percentage of the risk for cataracts are due to radiation, and how to best develop countermeasures to protect flight crews from radiation bioeffects in the future.

Convergent Evolution Associated with Habitat Decouples Phenotype from Phylogeny in a Clade of Lizards

PubMed Central

Edwards, Shelley; Vanhooydonck, Bieke; Herrel, Anthony; Measey, G. John; Tolley, Krystal A.

2012-01-01

Convergent evolution can explain similarity in morphology between species, due to selection on a fitness-enhancing phenotype in response to local environmental conditions. As selective pressures on body morphology may be strong, these have confounded our understanding of the evolutionary relationships between species. Within the speciose African radiation of lacertid lizards (Eremiadini), some species occupy a narrow habitat range (e.g. open habitat, cluttered habitat, strictly rupicolous, or strictly psammophilic), which may exert strong selective pressures on lizard body morphology. Here we show that the overall body plan is unrelated to shared ancestry in the African radiation of Eremiadini, but is instead coupled to habitat use. Comprehensive Bayesian and likelihood phylogenies using multiple representatives from all genera (2 nuclear, 2 mitochondrial markers) show that morphologically convergent species thought to represent sister taxa within the same genus are distantly related evolutionary lineages (Ichnotropis squamulosa and Ichnotropis spp.; Australolacerta rupicola and A. australis). Hierarchical clustering and multivariate analysis of morphological characters suggest that body, and head, width and height (stockiness), all of which are ecologically relevant with respect to movement through habitat, are similar between the genetically distant species. Our data show that convergence in morphology, due to adaptation to similar environments, has confounded the assignment of species leading to misidentification of the taxonomic position of I. squamulosa and the Australolacerta species. PMID:23251601

Heterozygote deficits in cyst plant-parasitic nematodes: possible causes and consequences.

PubMed

Montarry, Josselin; Jan, Pierre-Loup; Gracianne, Cecile; Overall, Andrew D J; Bardou-Valette, Sylvie; Olivier, Eric; Fournet, Sylvain; Grenier, Eric; Petit, Eric J

2015-04-01

Deviations of genotypic frequencies from Hardy-Weinberg equilibrium (HWE) expectations could reveal important aspects of the biology of populations. Deviations from HWE due to heterozygote deficits have been recorded for three plant-parasitic nematode species. However, it has never been determined whether the observed deficits were due (i) to the presence of null alleles, (ii) to a high level of consanguinity and/or (iii) to a Wahlund effect. The aim of the present work was, while taking into the possible confounding effect of null alleles, to disentangle consanguinity and Wahlund effect in natural populations of those three economically important cyst nematodes using microsatellite markers: Globodera pallida, G. tabacum and Heterodera schachtii, pests of potato, tobacco and sugar beet, respectively. The results show a consistent pattern of heterozygote deficiency in the three nematode species sampled at the spatial scale of the host plant. We demonstrate that the prevalence of null alleles is weak and that heterozygote deficits do not have a single origin. Our results suggested that it is restricted dispersal that leads to heterozygote deficits through both consanguinity and substructure, which effects can be linked to soil movement, cyst density, and the number of generations per year. We discuss potential implications for the durability of plant resistances that are used to protect crops against parasites in which mating between relatives occur. While consanguineous mating leads to homozygosity at all loci, including loci governing avirulence/virulence, which favours the expression of virulence when recessive, the Wahlund effect is expected to have no particular effect on the adaptation of nematodes to resistances. © 2015 John Wiley & Sons Ltd.

Deconstructing the smoking-preeclampsia paradox through a counterfactual framework.

PubMed

Luque-Fernandez, Miguel Angel; Zoega, Helga; Valdimarsdottir, Unnur; Williams, Michelle A

2016-06-01

Although smoking during pregnancy may lead to many adverse outcomes, numerous studies have reported a paradoxical inverse association between maternal cigarette smoking during pregnancy and preeclampsia. Using a counterfactual framework we aimed to explore the structure of this paradox as being a consequence of selection bias. Using a case-control study nested in the Icelandic Birth Registry (1309 women), we show how this selection bias can be explored and corrected for. Cases were defined as any case of pregnancy induced hypertension or preeclampsia occurring after 20 weeks' gestation and controls as normotensive mothers who gave birth in the same year. First, we used directed acyclic graphs to illustrate the common bias structure. Second, we used classical logistic regression and mediation analytic methods for dichotomous outcomes to explore the structure of the bias. Lastly, we performed both deterministic and probabilistic sensitivity analysis to estimate the amount of bias due to an uncontrolled confounder and corrected for it. The biased effect of smoking was estimated to reduce the odds of preeclampsia by 28 % (OR 0.72, 95 %CI 0.52, 0.99) and after stratification by gestational age at delivery (<37 vs. ≥37 gestation weeks) by 75 % (OR 0.25, 95 %CI 0.10, 0.68). In a mediation analysis, the natural indirect effect showed and OR > 1, revealing the structure of the paradox. The bias-adjusted estimation of the smoking effect on preeclampsia showed an OR of 1.22 (95 %CI 0.41, 6.53). The smoking-preeclampsia paradox appears to be an example of (1) selection bias most likely caused by studying cases prevalent at birth rather than all incident cases from conception in a pregnancy cohort, (2) omitting important confounders associated with both smoking and preeclampsia (preventing the outcome to develop) and (3) controlling for a collider (gestation weeks at delivery). Future studies need to consider these aspects when studying and interpreting the association between smoking and pregnancy outcomes.

Acylated and unacylated ghrelin do not directly stimulate glucose transport in isolated rodent skeletal muscle.

PubMed

Cervone, Daniel T; Dyck, David J

2017-07-01

Emerging evidence implicates ghrelin, a gut-derived, orexigenic hormone, as a potential mediator of insulin-responsive peripheral tissue metabolism. However, in vitro and in vivo studies assessing ghrelin's direct influence on metabolism have been controversial, particularly due to confounding factors such as the secondary rise in growth hormone (GH) after ghrelin injection. Skeletal muscle is important in the insulin-stimulated clearance of glucose, and ghrelin's exponential rise prior to a meal could potentially facilitate this. This study was aimed at elucidating any direct stimulatory action that ghrelin may have on glucose transport and insulin signaling in isolated rat skeletal muscle, in the absence of confounding secondary factors. Oxidative soleus and glycolytic extensor digitorum longus skeletal muscles were isolated from male Sprague Dawley rats in the fed state and incubated with various concentrations of acylated and unacylated ghrelin in the presence or absence of insulin. Ghrelin did not stimulate glucose transport in either muscle type, with or without insulin. Moreover, GH had no acute, direct stimulatory effect on either basal or insulin-stimulated muscle glucose transport. In agreement with the lack of observed effect on glucose transport, ghrelin and GH also had no stimulatory effect on Ser 473 AKT or Thr 172 AMPK phosphorylation, two key signaling proteins involved in glucose transport. Furthermore, to our knowledge, we are among the first to show that ghrelin can act independent of its receptor and cause an increase in calmodulin-dependent protein kinase 2 (CaMKII) phosphorylation in glycolytic muscle, although this was not associated with an increase in glucose transport. We conclude that both acylated and unacylated ghrelin have no direct, acute influence on skeletal muscle glucose transport. Furthermore, the immediate rise in GH in response to ghrelin also does not appear to directly stimulate glucose transport in muscle. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

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

Effects of multiple predator species on green treefrog (Hyla cinerea) tadpoles

USGS Publications Warehouse

Gunzburger, M.S.; Travis, J.

2005-01-01

Prey species that occur across a range of habitats may be exposed to variable communities of multiple predator species across habitats. Predicting the combined effects of multiple predators can be complex. Many experiments evaluating the effects of multiple predators on prey confound either variation in predator density with predator identity or variation in relative predator frequency with overall predation rates. We develop a new experimental design of factorial predator combinations that maintains a constant expected predation rate, under the null hypothesis of additive predator effects. We implement this design to evaluate the combined effects of three predator species (bass, aeshnid and libellulid odonate naiads) on mortality rate of a prey species, Hyla cinerea (Schneider, 1799) tadpoles, that occurs across a range of aquatic habitats. Two predator treatments (libellulid and aeshnid + libellulid) resulted in lower tadpole mortality than any of the other predator treatments. Variation in tadpole mortality across treatments was not related to coarse variation in microhabitat use, but was likely due to intraguild predation, which occurred in all predator treatments. Hyla cinerea tadpoles have constant, low survival values when exposed to many different combinations of predator species, and predation rate probably increases linearly with predator density.

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.

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

Exposure to aircraft and road traffic noise and associations with heart disease and stroke in six European countries: a cross-sectional study

PubMed Central

2013-01-01

Background Although a number of studies have found an association between aircraft noise and hypertension, there is a lack of evidence on associations with other cardiovascular disease. For road traffic noise, more studies are available but the extent of possible confounding by air pollution has not been established. Methods This study used data from the Hypertension and Environmental Noise near Airports (HYENA) study. Cross-sectional associations between self-reported ‘heart disease and stroke’ and aircraft noise and road traffic noise were examined using data collected between 2004 and 2006 on 4712 participants (276 cases), who lived near airports in six European countries (UK, Germany, Netherlands, Sweden, Greece, Italy). Data were available to assess potential confounding by NO2 air pollution in a subsample of three countries (UK, Netherlands, Sweden). Results An association between night-time average aircraft noise and ‘heart disease and stroke’ was found after adjustment for socio-demographic confounders for participants who had lived in the same place for ≥ 20 years (odds ratio (OR): 1.25 (95% confidence interval (CI) 1.03, 1.51) per 10 dB (A)); this association was robust to adjustment for exposure to air pollution in the subsample. 24 hour average road traffic noise exposure was associated with ‘heart disease and stroke’ (OR: 1.19 (95% CI 1.00, 1.41), but adjustment for air pollution in the subsample suggested this may have been due to confounding by air pollution. Statistical assessment (correlations and variance inflation factor) suggested only modest collinearity between noise and NO2 exposures. Conclusions Exposure to aircraft noise over many years may increase risks of heart disease and stroke, although more studies are needed to establish how much the risks associated with road traffic noise may be explained by air pollution. PMID:24131577

Comorbidities confounding the outcomes of surgery for third window syndrome: Outlier analysis

PubMed Central

Mackay‐Promitas, Heather T.; Demirel, Shaban; Gianoli, Gerard J.; Gizzi, Martin S.; Carter, Dale M.; Siker, David A.

2017-01-01

Objective Patients with third window syndrome and superior semicircular canal dehiscence (SSCD) symptoms whose surgical outcomes placed them as outliers were systematically studied to determine comorbidities that were responsible for their poor outcomes due to these confounding factors. Study Design Observational analytic case‐control study in a tertiary referral center. Methods Twelve adult patients with clinical SSCD syndrome underwent surgical management and had outcomes that did not resolve all of their subjective symptoms. In addition to one of the neurotologists, 2 neurologists (one specializing in migraine and the other a neuro‐ophthalmologist), and a psychologist clinician‐investigator completed comprehensive evaluations. Neuropsychology test batteries included: the Millon Behavioral Medicine Diagnostic; Patient Health Questionnaire (PHQ‐9) and Generalized Anxiety Disorder Screener (GAD‐7); Adverse Childhood Experiences Scale; the Wide Range Assessment of Memory and Learning, including the 3 domains of verbal memory, visual memory, and attention/concentration; Wechsler Adult Intelligence Scale; and the Delis‐Kaplan Executive Function System. The control cohort was comprised of 17 participants who previously underwent surgery for third window syndrome that resulted in the expected outcomes of resolution of their third window syndrome symptoms and cognitive dysfunction. Results There was a high rate of psychological comorbidity (n = 6) in the outlier cohort; multiple traumatic brain injuries were also a confounding element (n = 10). One patient had elevated cerebrospinal fluid (CSF) pressure requiring ventriculoperitoneal shunting to control the recurrence of dehiscence and one patient with a drug‐induced Parkinson‐like syndrome and idiopathic progressive neurological degenerative process. Conclusions Components of the Millon Behavioral Medicine Diagnostic, PHQ‐9 and GAD‐7 results suggest that these instruments would be useful as screening tools preoperatively to identify psychological comorbidities that could confound outcomes. The identification of these comorbid psychological as well as other neurological degenerative disease processes led to alternate clinical management pathways for these patients. Level of Evidence 2b. PMID:29094067

Correction of odds ratios in case-control studies for exposure misclassification with partial knowledge of the degree of agreement among experts who assessed exposures.

PubMed

Burstyn, Igor; Gustafson, Paul; Pintos, Javier; Lavoué, Jérôme; Siemiatycki, Jack

2018-02-01

Estimates of association between exposures and diseases are often distorted by error in exposure classification. When the validity of exposure assessment is known, this can be used to adjust these estimates. When exposure is assessed by experts, even if validity is not known, we sometimes have information about interrater reliability. We present a Bayesian method for translating the knowledge of interrater reliability, which is often available, into knowledge about validity, which is often needed but not directly available, and applying this to correct odds ratios (OR). The method allows for inclusion of observed potential confounders in the analysis, as is common in regression-based control for confounding. Our method uses a novel type of prior on sensitivity and specificity. The approach is illustrated with data from a case-control study of lung cancer risk and occupational exposure to diesel engine emissions, in which exposure assessment was made by detailed job history interviews with study subjects followed by expert judgement. Using interrater agreement measured by kappas (κ), we estimate sensitivity and specificity of exposure assessment and derive misclassification-corrected confounder-adjusted OR. Misclassification-corrected and confounder-adjusted OR obtained with the most defensible prior had a posterior distribution centre of 1.6 with 95% credible interval (Crl) 1.1 to 2.6. This was on average greater in magnitude than frequentist point estimate of 1.3 (95% Crl 1.0 to 1.7). The method yields insights into the degree of exposure misclassification and appears to reduce attenuation bias due to misclassification of exposure while the estimated uncertainty increased. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Exploring associations between prenatal solvent exposures and teenage drug and alcohol use: a retrospective cohort study.

PubMed

Gallagher, Lisa G; Webster, Thomas F; Aschengrau, Ann

2017-03-11

Investigating the effects of prenatal and childhood exposures on behavioral health outcomes in adolescence is challenging given the lengthy period between the exposure and outcomes. We conducted a retrospective cohort study in Cape Cod, Massachusetts to evaluate the impact of prenatal and early childhood exposure to tetrachloroethylene (PCE)-contaminated drinking water on the occurrence of risk-taking behaviors as a teenager. An increased occurrence of risk-taking behaviors, particularly illicit drug use, was observed in those highly exposed to PCE. We hypothesized that there may be other sources of prenatal solvent exposure such as maternal consumption of alcoholic beverages during pregnancy which might modify the previously observed associations between PCE and risk-taking behaviors and so we conducted an exploratory analysis using available cohort data. The current report presents the results of these analyses and describes the difficulties in conducting research on long-term behavioral effects of early life exposures. The exploratory analysis compared a referent group of subjects with no early life exposure to PCE or alcohol (n = 242) to subjects with only alcohol exposure (n = 201), subjects with only PCE exposure (n = 361), and subjects with exposure to both PCE and alcohol (n = 302). Surveys completed by the subject's mother included questions on prenatal alcoholic beverage consumption and available confounding variables such as cigarette smoking and marijuana use. Surveys completed by the subjects included questions on risk-taking behaviors such as alcoholic beverage consumption and illicit drug use as a teenager and available confounding variables. PCE exposure was modeled using a leaching and transport algorithm embedded in water distribution system modeling software that estimated the amount of PCE delivered to a subject's residence during gestation and early childhood. Subjects with early life exposure to both PCE and alcohol had an increased risk of using two or more major drugs as a teen (RR = 1.9 (95% CI 1.2, 3.0)) compared to unexposed subjects. Increased risks for only PCE exposure (RR = 1.6 (95% CI 1.0, 2.4) and only alcohol exposure (RR = 1.3 (95% CI 0.7, 2.1)) were also evident but were smaller than the increased risk associated with both exposures. While available confounding variables were controlled, many relevant social risk factors were not obtained due to limitations in the retrospective study design. This exploratory analysis found evidence for an additive effect of early life exposure to PCE and alcohol on the risk of use of multiple illicit drugs as a teenager. Because of numerous limitations in this retrospective study, further research is needed to examine longstanding behavioral effects of early life exposures. To be most informative, this research should involve long-term prospective data collection.

Stratified randomization controls better for batch effects in 450K methylation analysis: a cautionary tale.

PubMed

Buhule, Olive D; Minster, Ryan L; Hawley, Nicola L; Medvedovic, Mario; Sun, Guangyun; Viali, Satupaitea; Deka, Ranjan; McGarvey, Stephen T; Weeks, Daniel E

2014-01-01

Batch effects in DNA methylation microarray experiments can lead to spurious results if not properly handled during the plating of samples. Two pilot studies examining the association of DNA methylation patterns across the genome with obesity in Samoan men were investigated for chip- and row-specific batch effects. For each study, the DNA of 46 obese men and 46 lean men were assayed using Illumina's Infinium HumanMethylation450 BeadChip. In the first study (Sample One), samples from obese and lean subjects were examined on separate chips. In the second study (Sample Two), the samples were balanced on the chips by lean/obese status, age group, and census region. We used methylumi, watermelon, and limma R packages, as well as ComBat, to analyze the data. Principal component analysis and linear regression were, respectively, employed to identify the top principal components and to test for their association with the batches and lean/obese status. To identify differentially methylated positions (DMPs) between obese and lean males at each locus, we used a moderated t-test. Chip effects were effectively removed from Sample Two but not Sample One. In addition, dramatic differences were observed between the two sets of DMP results. After "removing" batch effects with ComBat, Sample One had 94,191 probes differentially methylated at a q-value threshold of 0.05 while Sample Two had zero differentially methylated probes. The disparate results from Sample One and Sample Two likely arise due to the confounding of lean/obese status with chip and row batch effects. Even the best possible statistical adjustments for batch effects may not completely remove them. Proper study design is vital for guarding against spurious findings due to such effects.

Stratified randomization controls better for batch effects in 450K methylation analysis: a cautionary tale

PubMed Central

Buhule, Olive D.; Minster, Ryan L.; Hawley, Nicola L.; Medvedovic, Mario; Sun, Guangyun; Viali, Satupaitea; Deka, Ranjan; McGarvey, Stephen T.; Weeks, Daniel E.

2014-01-01

Background: Batch effects in DNA methylation microarray experiments can lead to spurious results if not properly handled during the plating of samples. Methods: Two pilot studies examining the association of DNA methylation patterns across the genome with obesity in Samoan men were investigated for chip- and row-specific batch effects. For each study, the DNA of 46 obese men and 46 lean men were assayed using Illumina's Infinium HumanMethylation450 BeadChip. In the first study (Sample One), samples from obese and lean subjects were examined on separate chips. In the second study (Sample Two), the samples were balanced on the chips by lean/obese status, age group, and census region. We used methylumi, watermelon, and limma R packages, as well as ComBat, to analyze the data. Principal component analysis and linear regression were, respectively, employed to identify the top principal components and to test for their association with the batches and lean/obese status. To identify differentially methylated positions (DMPs) between obese and lean males at each locus, we used a moderated t-test. Results: Chip effects were effectively removed from Sample Two but not Sample One. In addition, dramatic differences were observed between the two sets of DMP results. After “removing” batch effects with ComBat, Sample One had 94,191 probes differentially methylated at a q-value threshold of 0.05 while Sample Two had zero differentially methylated probes. The disparate results from Sample One and Sample Two likely arise due to the confounding of lean/obese status with chip and row batch effects. Conclusion: Even the best possible statistical adjustments for batch effects may not completely remove them. Proper study design is vital for guarding against spurious findings due to such effects. PMID:25352862

Joint Effects of Ambient Air Pollutants on Pediatric Asthma ...

EPA Pesticide Factsheets

Background: Because ambient air pollution exposure occurs in the form of mixtures, consideration of joint effects of multiple pollutants may advance our understanding of air pollution health effects. Methods: We assessed the joint effect of selected ambient air pollutant combinations (groups of oxidant, secondary, traffic, power plant, and criteria pollutants constructed using combinations of criteria gases, fine particulate matter (PM2.5) and PM2.5 components) on warm season pediatric asthma emergency department (ED) visits in Atlanta during 1998-2004. Joint effects were assessed using multi-pollutant Poisson generalized linear models controlling for time trends, meteorology and daily non-asthma respiratory ED visit counts. Rate ratios (RR) were calculated for the combined effect of an interquartile-range increment in the concentration of each pollutant. Results: Increases in all of the selected pollutant combinations were associated with increases in pediatric asthma ED visits [e.g., joint effect rate ratio=1.13 (95% confidence interval 1.06-1.21) for criteria pollutants (including ozone, carbon monoxide, nitrogen dioxide, sulfur dioxide, and PM2.5)]. Joint effect estimates were smaller than estimates calculated based on summing results from single-pollutant models, due to control for confounding. Compared with models without interactions, joint effect estimates from models including first-order pollutant interactions were similar for oxidant a

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.

Multisample adjusted U-statistics that account for confounding covariates.

PubMed

Satten, Glen A; Kong, Maiying; Datta, Somnath

2018-06-19

Multisample U-statistics encompass a wide class of test statistics that allow the comparison of 2 or more distributions. U-statistics are especially powerful because they can be applied to both numeric and nonnumeric data, eg, ordinal and categorical data where a pairwise similarity or distance-like measure between categories is available. However, when comparing the distribution of a variable across 2 or more groups, observed differences may be due to confounding covariates. For example, in a case-control study, the distribution of exposure in cases may differ from that in controls entirely because of variables that are related to both exposure and case status and are distributed differently among case and control participants. We propose to use individually reweighted data (ie, using the stratification score for retrospective data or the propensity score for prospective data) to construct adjusted U-statistics that can test the equality of distributions across 2 (or more) groups in the presence of confounding covariates. Asymptotic normality of our adjusted U-statistics is established and a closed form expression of their asymptotic variance is presented. The utility of our approach is demonstrated through simulation studies, as well as in an analysis of data from a case-control study conducted among African-Americans, comparing whether the similarity in haplotypes (ie, sets of adjacent genetic loci inherited from the same parent) occurring in a case and a control participant differs from the similarity in haplotypes occurring in 2 control participants. Copyright © 2018 John Wiley & Sons, Ltd.

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…

PHOSPHATE BINDER USE AND MORTALITY AMONG HEMODIALYSIS PATIENTS IN THE DOPPS: EVALUATION OF POSSIBLE CONFOUNDING BY NUTRITIONAL STATUS

PubMed Central

Lopes, Antonio Alberto; Tong, Lin; Thumma, Jyothi; Li, Yun; Fuller, Douglas S.; Morgenstern, Hal; Bommer, Jürgen; Kerr, Peter G; Tentori, Francesca; Akiba, Takashi; Gillespie, Brenda; Robinson, Bruce M.; Port, Friedrich K; Pisoni, Ronald L.

2014-01-01

Background Poor nutritional status and both hyperphosphatemia and hypophosphatemia are associated with increased mortality in maintenance hemodialysis (MHD) patients. We assessed associations of PB prescription with survival and indicators of nutritional status among (MHD) patients. Study Design Prospective cohort study (DOPPS) 1996 to 2008. Setting and Participants 23,898 MHD patients at 923 facilities in 12 countries. Predictors Patient-level PB prescription; and case-mix-adjusted facility percentage PB prescription using an instrumental-variable analysis. Outcome All-cause mortality. Results Overall, 88% of patients were prescribed PBs. The distributions of age, comorbidities and other characteristics showed small differences between facilities with higher and lower percentage PB prescription. Patient-level PB prescription was strongly associated at baseline with indicators of better nutrition, i.e., higher serum creatinine, albumin, normalized protein-catabolic rate, BMI and absence of cachectic appearance. Overall, patients prescribed PBs displayed 25% lower mortality (hazard ratio [HR] = 0.75, 95% confidence interval [CI] = 0.68–0.83) when adjusted for serum phosphorus and other covariates; further adjustment for nutritional indicators attenuated this association (HR = 0.88, 95% CI = 0.80–0.97). This inverse association, however, was observed only for patients with serum phosphorus ≥3.5mg/dL. In the instrumental-variable analysis, case-mix-adjusted facility percentage PB prescription (range: 23–100%) was positively associated with better nutritional status and inversely associated with mortality (HR for 10% more PB = 0.93, 95% CI = 0.89–0.96). Further adjustment for nutritional indicators reduced this association to HR = 0.95 (95% CI = 0.92–0.99). Limitations Results were based on PB prescription; PB and nutritional data were cross-sectional; dietary restriction was not assessed; observational design limits causal inference due to possible residual confounding. Conclusions Longer survival and better nutritional status were observed for MHD patients prescribed PBs and in facilities with greater percentage PB prescription. Understanding the mechanisms for explaining this effect and ruling out possible residual confounding require additional research. PMID:22385781

The Effect of Serum Sodium on Survival in Patients Treated by Peritoneal Dialysis in the United Kingdom.

PubMed

Al-Chidadi, Asmaa; Nitsch, Dorothea; Davenport, Andrew

♦ BACKGROUND: Studies in hemodialysis patients suggest that hyponatremia is associated with increased mortality. However, results from peritoneal dialysis (PD) patients are discordant. We wished to establish whether there was an association between serum sodium and mortality risk in PD patients. ♦ METHODS: We analyzed 3,108 PD patients enrolled at day 90 of renal replacement therapy (RRT) into the UK Renal Registry (UKRR) data base with available serum sodium measurements (in 3 groups: ≤ 137, 138 - 140, ≥ 141 mmol/L) who were then followed up until death or the censoring date (31 December 2012). Analysis used Cox-regression with adjustment for age, sex, year of starting RRT, primary renal disease, serum albumin, smoking, and comorbidities. ♦ RESULTS: Unadjusted mortality rates were 118.6/1,000 person-years (py), 83.4/1,000 py, and 83.5/1,000 py for the lowest, middle, and highest serum sodium tertiles, respectively. After adjustment for covariates, patients in the lowest serum sodium group had almost 50% increased risk of dying compared with those with the highest serum sodium (hazard ratio [HR] 1.49, confidence interval [CI]:1.28 - 1.74), with a graded association between serum sodium and mortality. The association of serum sodium with mortality varied by age (p interaction < 0.001), and whilst this association attenuated after adjustment for confounding variables in the older age groups (55 - 64, and > 65 years), it remained in the younger age group of 18 - 54 years (HR 2.24 [1.36 - 3.70] in the lowest compared with the highest sodium tertile). ♦ CONCLUSIONS: Lower serum sodium concentrations at the start of RRT in PD patients are associated with increased risk of mortality. Whilst this association may well be due to confounding in the older age groups, the persistent strong association between hyponatremia and mortality in the younger age group after adjustment for the available confounders suggests that prospective studies are required to assess whether active intervention to maintain serum sodium changes outcomes. Copyright © 2017 International Society for Peritoneal Dialysis.

Inequality in diabetes-related hospital admissions in England by socioeconomic deprivation and ethnicity: facility-based cross-sectional analysis.

PubMed

Nishino, Yoshitaka; Gilmour, Stuart; Shibuya, Kenji

2015-01-01

To investigate the effect of social deprivation and ethnicity on inpatient admissions due to diabetes in England. Facility-based cross-sectional analysis. National Health Service (NHS) trusts in England reporting inpatient admissions with better than 80% data reporting quality from 2010-2011 (355 facilities). Non-obstetric patients over 16 years old in all NHS facilities in England. The sample size after exclusions was 5,147,859 all-cause admissions. The relative risk of inpatient admissions and readmissions due to diabetes adjusted for confounders. There were 445,504 diabetes-related hospital admissions in England in 2010, giving a directly (age-sex) standardized rate of 1049.0 per 100,000 population (95% confidence interval (CI): 1046.0-1052.1). The relative risk of inpatient admission in the most deprived quintile was 2.08 times higher than that of the least deprived quintile (95% CI: 2.02-2.14), and the effect of deprivation varied across ethnicities. About 30.1% of patients admitted due to diabetes were readmitted at least once due to diabetes. South Asians showed 2.62 times (95% CI: 2.51-2.74) higher admission risk. Readmission risk increased with IMD among white British but not other ethnicities. South Asians showed slightly lower risk of readmission than white British (0.86, 95% CI: 0.80-0.94). More deprived areas had higher rates of inpatient admissions and readmissions due to diabetes. South Asian British showed higher admission risk and lower readmission risk than white British. However, there was almost no difference by ethnicity in readmission due to diabetes. Higher rates of admission among deprived people may not necessarily reflect higher prevalence, but higher admission rates in south Asian British may be explained by their higher prevalence because their lower readmission risk suggests no inequality in primary care to prevent readmission. Better interventions in poorer areas, are needed to reduce these inequalities.

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

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.

Mood disorders: A potential link between ghrelin and leptin on human body?

PubMed

Zarouna, Stalo; Wozniak, Greta; Papachristou, Anastasia Ioannis

2015-05-20

Leptin and ghrelin are two hormones associated with multiple physiological functions, especially energy balance. Leptin is an adipocyte-secreted hormone discovered in 1950 and ghrelin which was found in 1999, is a peptide hormone produced and secreted in the stomach. A number of previous studies showed that these hormones could be associated with different types of mood disorders. The results of previous studies, nevertheless, are confounded by diverse sample selection and different methodologies. A search for related articles in the PubMed database was attempted. The search covered studies, reports, reviews and editorials published in the last ten years. Older references served as auxiliary sources for comparison purposes. However, due to the different results of the studies, there is a need for more investigation in order to establish the exact biochemical mechanisms that are responsible for these diseases and ghrelin's and leptin's effects on mood.