@article {646635, title = {Assessing Knowledge, Attitudes, and Practices towards Causal Directed Acyclic Graphs among Epidemiologists and Medical Researchers: a qualitative research project}, journal = {medRxiv}, year = {Working Paper}, abstract = {Background: Estimating the strength of causal effects is an important component of epidemiologic research, and causal graphs provide a key tool for optimizing the validity of these effect estimates. Although a large literature exists on the mathematical theory underlying the use of causal graphs, including directed acyclic graphs, to assess and describe causal assumptions, and translate these assumptions into appropriate statistical analysis plans, less literature exists to aid applied researchers in understanding how best to develop and use causal graphs in their research projects. Objective We sought to understand this gap by surveying practicing epidemiologists and medical researchers on their knowledge, level of interest, attitudes, and practices towards the use of causal graphs in applied epidemiology and health research. Methods We conducted an anonymous survey of self-identified epidemiology and health researchers via Twitter and via the Society of Epidemiologic Research membership listserv. The survey was conducted using Qualtrics and asked a series of multiple choice and open-ended questions about causal graphs. Results In total, 439 responses were collected. Overall, 62\% reported being comfortable with using causal graphs, and 60\% reported using them 9sometimes9, 9often9, or 9always9 in their research. About 70\% of respondents had received formal training on causal graphs (typically causal directed acyclic graphs). Having received any training appeared to improve comprehension of the underlying assumptions of causal graphs. Forty percent of respondents who did not use causal graphs reported lack of knowledge\ {\textellipsis}}, url = {https://www.medrxiv.org/content/10.1101/2020.01.17.20017939v1.abstract}, author = {Ruby M Barnard-Mayers and Ellen Childs and Laura Corlin and Ellen Caniglia and Matthew Fox and John P Donnelly and Murray, Eleanor J} } @article {646634, title = {Guidelines for estimating causal effects in pragmatic randomized trials}, journal = {arXiv preprint arXiv:1911.06030}, year = {Working Paper}, abstract = {Pragmatic randomized trials are designed to provide evidence for clinical decision-making rather than regulatory approval. Common features of these trials include the inclusion of heterogeneous or diverse patient populations in a wide range of care settings, the use of active treatment strategies as comparators, unblinded treatment assignment, and the study of long-term, clinically relevant outcomes. These features can greatly increase the usefulness of the trial results for patients, clinicians, and other stakeholders. However, these features also introduce an increased risk of non-adherence, which reduces the value of the intention-to-treat effect as a patient-centered measure of causal effect. In these settings, the per-protocol effect provides useful complementary information for decision making. Unfortunately, there is little guidance for valid estimation of the per-protocol effect. Here, we present our full guidelines for analyses of pragmatic trials that will result in more informative causal inferences for both the intention-to-treat effect and the per-protocol effect.}, url = {https://arxiv.org/abs/1911.06030}, author = {Murray, Eleanor J and Sonja S Swanson and Hernan, Miguel A} } @article {646633, title = {A Note on Estimating Optimal Dynamic Treatment Strategies Under Resource Constraints Using Dynamic Marginal Structural Models}, journal = {arXiv preprint arXiv:1903.06488}, year = {Working Paper}, abstract = {Existing strategies for determining the optimal treatment or monitoring strategy typically assume unlimited access to resources. However, when a health system has resource constraints, such as limited funds, access to medication, or monitoring capabilities, medical decisions must balance impacts on both individual and population health outcomes. That is, decisions should account for competition between individuals in resource usage. One simple solution is to estimate the (counterfactual) resource usage under the possible interventions and choose the optimal strategy for which resource usage is within acceptable limits. We propose a method to identify the optimal dynamic intervention strategy that leads to the best expected health outcome accounting for a health system{\textquoteright}s resource constraints. We then apply this method to determine the optimal dynamic monitoring strategy for people living with HIV when resource limits on monitoring exist using observational data from the HIV-CAUSAL Collaboration.}, url = {https://arxiv.org/abs/1903.06488}, author = {Caniglia, Ellen C and Murray, Eleanor J and Hernan, Miguel A and Shahn, Zach} } @article {646632, title = {Use of directed acyclic graphs (DAGs) in applied health research: review and recommendations}, journal = {medRxiv}, year = {Working Paper}, abstract = {BACKGROUND: Directed acyclic graphs (DAGs) are an increasingly popular approach for identifying confounding variables that require adjustment when estimating causal effects. This review examined the use of DAGs in applied health research to inform recommendations for improving their transparency and utility in future research. METHODS: Original health research articles published during 1999-2017 mentioning "directed acyclic graphs" or similar or citing DAGitty were identified from Scopus, Web of Science, Medline, and Embase. Data were extracted on the reporting of: estimands, DAGs, and adjustment sets, alongside the characteristics of each article{\textquoteright}s largest DAG. RESULTS: A total of 234 articles were identified that reported using DAGs. A fifth (n=48, 21\%) reported their target estimand(s) and half (n=115, 48\%) reported the adjustment set(s) implied by their DAG(s). Two-thirds of the articles (n=144, 62\%) made at least one DAG available. Diagrams varied in size but averaged 12 nodes (IQR: 9-16, range: 3-28) and 29 arcs (IQR: 19-42, range: 3-99). The median saturation (i.e. percentage of total possible arcs) was 46\% (IQR: 31-67, range: 12-100). 37\% (n=53) of the DAGs included unobserved variables, 17\% (n=25) included super-nodes (i.e. nodes containing more than one variable, and a 34\% (n=49) were arranged so the constituent arcs flowed in a consistent direction. CONCLUSIONS: There is substantial variation in the use and reporting of DAGs in applied health research. Although this partly reflects their flexibility, it also highlight some potential areas for improvement. This review hence offers several recommendations to improve the reporting and use of DAGs in future research.}, url = {https://www.medrxiv.org/content/10.1101/2019.12.20.19015511v1.abstract}, author = {Peter WG Tennant and Wendy J Harrison and Murray, Eleanor J and Kellyn F Arnold and Laurie Berrie and Matthew P Fox and Sarah C Gadd and Claire Keeble and Lynsie R Ranker and Johannes Textor and Georgia D Tomova and Mark S Gilthorpe and George TH Ellison} } @article {646636, title = {Adherence-adjustment in placebo-controlled randomized trials: An application to the candesartan in heart failure randomized trial}, journal = {Contemporary Clinical Trials}, year = {In Press}, abstract = {BackgroundThe per-protocol effect provides important information in randomized trials with incomplete adherence. Yet, because valid estimation typically requires adjustment for prognostic factors that predict adherence, per-protocol effect estimates are often met with skepticism. In placebo-controlled trials, however, the validity of adjustment can be indirectly verified by demonstrating no association between adherence and the outcome among the placebo arm. Here, we describe a two-stage procedure in which we first adjust for time-varying adherence in the placebo arm and then use a similar procedure to estimate the per-protocol effect.MethodsWe use the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) randomized trial. First, we compare adherers versus non-adherers in the placebo arm, adjusting for pre- and post-randomization variables. Second, we use models validated in the placebo arm to estimate the per-protocol effect of adherence to candesartan versus placebo in the full trial.FindingsWe successfully estimated no association between adherence and mortality in the placebo arm; hazard ratio: 0.91 (95\% CI: 0.51, 2.52). We then estimated the per-protocol effect under two sets of protocol-defined stopping criteria after adjustment for post-randomization confounders. The mortality hazard ratio estimates ranged from 0.91 to 0.93 for the per-protocol effect estimates, similar to the intention-to-treat effect estimates.InterpretationAdherence adjustment in the CHARM trial is feasible when appropriate assumptions about missing data and confounding are made. These assumptions cannot be verified but can be supported through the use of placebo-arm adherence assessment.}, url = {https://doi.org/10.1016/j.cct.2020.105937}, author = {Murray, Eleanor J and Brian L Claggett and Bradi Granger and Solomon, Scott D and Hernan, Miguel A} } @article {642295, title = {Is this a Portrait of John Graunt? An Art History Mystery}, journal = {American Journal of Epidemiology}, year = {In Press}, url = {https://academic.oup.com/aje/advance-article/doi/10.1093/aje/kwz212/5580104?guestAccessKey=91282814-8c0a-4279-a918-efe5be46d76d}, author = {Murray, Eleanor J and Farland, Leslie V and Caniglia, Ellen C and Dorans, Kirsten S and Natalie C DuPre and Katherine C Hughes and Iris Y Kim and Pernar, Claire H and Lauren J Tanz and Rachel M Zack} } @article {646637, title = {The Challenges of Parameterizing Direct Effects in Individual-Level Simulation Models}, journal = {Medical Decision Making}, volume = {40}, number = {1}, year = {2020}, pages = {106-111}, url = {https://doi.org/10.1177/0272989X19894940}, author = {Murray, Eleanor J and Robins, James M and George R Seage III and Freedberg, Kenneth A and Hernan, Miguel A} } @article {642292, title = {Guidance for a causal comparative effectiveness analysis emulating a target trial based on big real world evidence: when to start statin treatment}, journal = {J Comp Eff Res}, volume = {8}, number = {12}, year = {2019}, month = {2019 Sep}, pages = {1013-1025}, abstract = { The aim of this project is to describe a causal (counterfactual) approach for analyzing when to start statin treatment to prevent cardiovascular disease using real-world evidence. We use directed acyclic graphs to operationalize and visualize the causal research question considering selection bias, potential time-independent and time-dependent confounding. We provide a study protocol following the {\textquoteright}target trial{\textquoteright} approach and describe the data structure needed for the causal assessment. The study protocol can be applied to real-world data, in general. However, the structure and quality of the database play an essential role for the validity of the results, and database-specific potential for bias needs to be explicitly considered.}, issn = {2042-6313}, doi = {10.2217/cer-2018-0103}, author = {Kuehne, Felicitas and Jahn, Beate and Conrads-Frank, Annette and Bundo, Marvin and Arvandi, Marjan and Endel, Florian and Popper, Niki and Endel, Gottfried and Urach, Christoph and Gyimesi, Michael and Murray, Eleanor J and Danaei, Goodarz and Thomas A Gaziano and Ankur Pandya and Siebert, Uwe} } @article {642293, title = {Interval-cohort designs and bias in the estimation of per-protocol effects: a simulation study}, journal = {Trials}, volume = {20}, number = {1}, year = {2019}, month = {2019 Sep 05}, pages = {552}, abstract = {BACKGROUND: Randomized trials are considered the gold standard for making inferences about the causal effects of treatments. However, when protocol deviations occur, the baseline randomization of the trial is no longer sufficient to ensure unbiased estimation of the per-protocol effect: post-randomization, time-varying confounders must be sufficiently measured and adjusted for in the analysis. Given the historical emphasis on intention-to-treat effects in randomized trials, measurement of post-randomization confounders is typically infrequent. This may induce bias in estimates of the per-protocol effect, even using methods such as inverse probability weighting, which appropriately account for time-varying confounders affected by past treatment. METHODS/DESIGN: In order to concretely illustrate the potential magnitude of bias due to infrequent measurement of time-varying covariates, we simulated data from a very large trial with a survival outcome and time-varying confounding affected by past treatment. We generated the data such that the true underlying per-protocol effect is null and under varying degrees of confounding (strong, moderate, weak). In the simulated data, we estimated per-protocol survival curves and associated contrasts using inverse probability weighting under monthly measurement of the time-varying covariates (which constituted complete measurement in our simulation), yearly measurement, as well as 3- and 6-month intervals. RESULTS: Using inverse probability weighting, we were able to recover the true null under the complete measurement scenario no matter the strength of confounding. Under yearly measurement intervals, the estimate of the per-protocol effect diverged from the null; inverse probability weighted estimates of the per-protocol 5-year risk ratio based on yearly measurement were 1.19, 1.12, and 1.03 under strong, moderate, and weak confounding, respectively. Bias decreased with measurement interval length. Under all scenarios, inverse probability weighted estimators were considerably less biased than a naive estimator that ignored time-varying confounding completely. CONCLUSIONS: Bias that arises from interval measurement designs highlights the need for planning in the design of randomized trials for collection of time-varying covariate data. This may come from more frequent in-person measurement or external sources (e.g., electronic medical record data). Such planning will provide improved estimates of the per-protocol effect through the use of methods that appropriately adjust for time-varying confounders.}, issn = {1745-6215}, doi = {10.1186/s13063-019-3577-z}, author = {Young, Jessica G and Vatsa, Rajet and Murray, Eleanor J and Hern{\'a}n, Miguel A} } @article {642294, title = {Methodological Challenges When Studying Distance to Care as an Exposure in Health Research}, journal = {Am J Epidemiol}, volume = {188}, number = {9}, year = {2019}, month = {2019 Sep 01}, pages = {1674-1681}, abstract = {Distance to care is a common exposure and proposed instrumental variable in health research, but it is vulnerable to violations of fundamental identifiability conditions for causal inference. We used data collected from the Botswana Birth Outcomes Surveillance study between 2014 and 2016 to outline 4 challenges and potential biases when using distance to care as an exposure and as a proposed instrument: selection bias, unmeasured confounding, lack of sufficiently well-defined interventions, and measurement error. We describe how these issues can arise, and we propose sensitivity analyses for estimating the degree of bias.}, issn = {1476-6256}, doi = {10.1093/aje/kwz121}, url = {https://academic.oup.com/aje/advance-article/doi/10.1093/aje/kwz121/5492131?guestAccessKey=d83fe774-0dd3-4839-b580-fd10fbabb9bf }, author = {Caniglia, Ellen C and Zash, Rebecca and Swanson, Sonja A and Wirth, Kathleen E and Diseko, Modiegi and Mayondi, Gloria and Lockman, Shahin and Mmalane, Mompati and Makhema, Joseph and Dryden-Peterson, Scott and Kponee-Shovein, Kal{\'e} Z and John, Oaitse and Murray, Eleanor J and Shapiro, Roger L} } @article {613390, title = {Patients and investigators preferred measures of absolute risk in subgroups for pragmatic randomized trials}, journal = {J Clin Epidemiol}, year = {2018}, month = {2018 Jun 29}, abstract = {OBJECTIVES: Pragmatic randomized trials are important tools for shared decision-making, but no guidance exists on patients{\textquoteright} preferences for types of causal information. We aimed to assess preferences of patients and investigators towards causal effects in pragmatic randomized trials. STUDY DESIGN AND SETTING: We: (a) held 3 focus groups with patients (n=23) in Boston, MA; (b) surveyed (n=12) and interviewed (n=5) investigators with experience conducting pragmatic trials; and (c) conducted a systematic literature review of pragmatic trials (n=63). RESULTS: Patients were distrustful of new-to-market medications unless substantially more effective than existing choices, preferred stratified absolute risks, and valued adherence-adjusted analyses when they expected to adhere. Investigators wanted both intention-to-treat and per-protocol effects, but felt methods for estimating per-protocol effects were lacking. When estimating per-protocol effects, many pragmatic trials used inappropriate methods to adjust for adherence and loss to follow-up. CONCLUSION: We make 4 recommendations for pragmatic trials to improve patient centeredness: (1) focus on superiority in effectiveness or safety, rather than noninferiority; (2) involve patients in specifying a priori subgroups; (3) report absolute measures of risk, and (4) complement intention-to-treat effect estimates with valid per-protocol effect estimates.}, issn = {1878-5921}, doi = {10.1016/j.jclinepi.2018.06.009}, url = {https://authors.elsevier.com/a/1XS1b3BcJPuv3w}, author = {Murray, Eleanor J and Caniglia, Ellen C and Swanson, Sonja A and Hern{\'a}ndez-D{\'\i}az, Sonia and Hern{\'a}n, Miguel A} } @article {606029, title = {Improved adherence adjustment in the Coronary Drug Project}, journal = {Trials}, volume = {19}, year = {2018}, pages = {158}, abstract = {BackgroundThe survival difference between adherers and non-adherers to placebo in the Coronary Drug Project has been used to support the thesis that adherence adjustment in randomized trials is not generally possible and, therefore, that only intention-to-treat analyses should be trusted. We previously demonstrated that adherence adjustment can be validly conducted in the Coronary Drug Project using a simplistic approach. Here, we re-analyze the data using an approach that takes full advantage of recent methodological developments.MethodsWe used inverse-probability weighted hazards models to estimate the 5-year survival and mortality risk when individuals in the placebo arm of the Coronary Drug Project adhere to at least 80\% of the drug continuously or never during the 5-year follow-up period.ResultsAdjustment for post-randomization covariates resulted in 5-year mortality risk difference estimates ranging from - 0.7 (95\% confidence intervals (CI), - 12.2, 10.7) to 4.5 (95\% CI, - 6.3, 15.3) percentage points.ConclusionsOur analysis confirms that appropriate adjustment for post-randomization predictors of adherence largely removes the association between adherence to placebo and mortality originally described in this trial.}, url = {https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-018-2519-5}, author = {Murray, Eleanor J and Hernan, Miguel A} } @article {585866, title = {Using observational data to calibrate simulation models}, journal = {Med Decis Making}, volume = {38}, number = {2}, year = {2018}, month = {2017 Nov 01}, pages = {212-24}, abstract = {BACKGROUND: Individual-level simulation models are valuable tools for comparing the impact of clinical or public health interventions on population health and cost outcomes over time. However, a key challenge is ensuring that outcome estimates correctly reflect real-world impacts. Calibration to targets obtained from randomized trials may be insufficient if trials do not exist for populations, time periods, or interventions of interest. Observational data can provide a wider range of calibration targets but requires methods to adjust for treatment-confounder feedback. We propose the use of the parametric g-formula to estimate calibration targets and present a case-study to demonstrate its application. METHODS: We used the parametric g-formula applied to data from the HIV-CAUSAL Collaboration to estimate calibration targets for 7-y risks of AIDS and/or death (AIDS/death), as defined by the Center for Disease Control and Prevention under 3 treatment initiation strategies. We compared these targets to projections from the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) model for treatment-na{\"\i}ve individuals presenting to care in the following year ranges: 1996 to 1999, 2000 to 2002, or 2003 onwards. RESULTS: The parametric g-formula estimated a decreased risk of AIDS/death over time and with earlier treatment. The uncalibrated CEPAC model successfully reproduced targets obtained via the g-formula for baseline 1996 to 1999, but over-estimated calibration targets in contemporary populations and failed to reproduce time trends in AIDS/death risk. Calibration to g-formula targets improved CEPAC model fit for contemporary populations. CONCLUSION: Individual-level simulation models are developed based on best available information about disease processes in one or more populations of interest, but these processes can change over time or between populations. The parametric g-formula provides a method for using observational data to obtain valid calibration targets and enables updating of simulation model inputs when randomized trials are not available.}, issn = {1552-681X}, doi = {10.1177/0272989X17738753}, url = {https://doi.org/10.1177/0272989X17738753}, author = {Murray, Eleanor J and Robins, James M and Seage, George R and Lodi, Sara and Hyle, Emily P and Reddy, Krishna P and Freedberg, Kenneth A and Hern{\'a}n, Miguel A} } @article {547341, title = {A comparison of agent-based models and the parametric g-formula for causal inference}, journal = {American Journal of Epidemiology}, volume = {186}, number = {2}, year = {2017}, pages = {131-42}, abstract = {Decision-making requires choosing from treatments on the basis of correctly estimated outcome distributions under each treatment. In the absence of randomized trials, 2 possible approaches are the parametric g-formula and agent-based models (ABMs). The g-formula has been used exclusively to estimate effects in the population from which data were collected, whereas ABMs are commonly used to estimate effects in multiple populations, necessitating stronger assumptions. Here, we describe potential biases that arise when ABM assumptions do not hold. To do so, we estimated 12-month mortality risk in simulated populations differing in prevalence of an unknown common cause of mortality and a time-varying confounder. The ABM and g-formula correctly estimated mortality and causal effects when all inputs were from the target population. However, whenever any inputs came from another population, the ABM gave biased estimates of mortality{\textemdash}and often of causal effects even when the true effect was null. In the absence of unmeasured confounding and model misspecification, both methods produce valid causal inferences for a given population when all inputs are from that population. However, ABMs may result in bias when extrapolated to populations that differ on the distribution of unmeasured outcome determinants, even when the causal network linking variables is identical.}, url = {https://academic.oup.com/aje/article/186/2/131/3904485/A-Comparison-of-AgentBased-Models-and-the?guestAccessKey=adfdec0c-35a6-489a-8de7-d89c6427f991}, author = {Eleanor J. Murray and Robins, James M. and George R. Seage, III and Kenneth A. Freedberg and Miguel A. Hernan} } @article {Murray07032016, title = {Adherence adjustment in the Coronary Drug Project: A call for better per-protocol effect estimates in randomized trials}, journal = {Clinical Trials}, volume = {13}, number = {4}, year = {2016}, pages = {372-8}, abstract = {Background: In many randomized controlled trials, patients and doctors are more interested in the per-protocol effect than in the intention-to-treat effect. However, valid estimation of the per-protocol effect generally requires adjustment for prognostic factors associated with adherence. These adherence adjustments have been strongly questioned in the clinical trials community, especially after 1980 when the Coronary Drug Project team found that adherers to placebo had lower 5-year mortality than non-adherers to placebo.Methods: We replicated the original Coronary Drug Project findings from 1980 and re-analyzed the Coronary Drug Project data using technical and conceptual developments that have become established since 1980. Specifically, we used logistic models for binary outcomes, decoupled the definition of adherence from loss to follow-up, and adjusted for pre-randomization covariates via standardization and for post-randomization covariates via inverse probability weighting.Results: The original Coronary Drug Project analysis reported a difference in 5-year mortality between adherers and non-adherers in the placebo arm of 9.4 percentage points. Using modern approaches, we found that this difference was reduced to 2.5 (95\% confidence interval: -2.1 to 7.0).Conclusion: Valid estimation of per-protocol effects may be possible in randomized clinical trials when analysts use appropriate methods to adjust for post-randomization variables.}, doi = {10.1177/1740774516634335}, url = {http://ctj.sagepub.com/content/early/2016/03/04/1740774516634335.abstract}, author = {Murray, Eleanor J and Hern{\'a}n, Miguel A} } @article {359711, title = {Non-modifiable worker and workplace risk factors contributing to workplace absence: A stakeholder-centred synthesis of systematic reviews.}, journal = {Work}, volume = {52}, number = {2}, year = {2015}, month = {2015 Aug 14}, pages = {353-73}, abstract = {BACKGROUND: Workplace stakeholders report the identification and translation of relevant high quality research to inform workplace disability policy and practice is a challenge. The present study engaged academic and community stakeholders in conducting a best evidence-synthesis to identify non-modifiable risk and protective worker and workplace factors impacting work-related absence across a variety of health conditions. OBJECTIVE: To identify non-modifiable worker and workplace disability risk and protective factors impacting work-related absence across common health conditions. METHODS: The research team searched Medline, Embase, CINAHL, The Cochrane Library, PsycINFO, BusinessSource-Complete, and ABI/Inform from 2000 to 2011. Quantitative, qualitative, or mixed methods systematic reviews of work-focused population were considered for inclusion. Two or more reviewers independently reviewed articles for inclusion and methodological screening. RESULTS: The search strategy, including expert input and grey literature, led to the identification of 2,467 unique records. From this initial search, 2325 were eliminated by title or abstract review, 142 articles underwent comprehensive review to assess for inclusion, 26 systematic reviews met eligibility criteria for this synthesis. For non-modifiable worker and workplace factors we found consistent evidence across two or more health conditions for increased risk of disability in situations where workers experience lower education, older age, emotional distress, poor personal functioning, decreased physical functioning, psychological symptoms, overweight status, and greater sick leave history. LIMITATIONS: Heterogeneity of existing literature due to differences in outcome measures, definitions and research designs limited ability to assess effect size and results reflect findings limited to English-language papers.}, issn = {1875-9270}, doi = {10.3233/WOR-152134}, author = {White, Marc I and Wagner, Shannon L and Schultz, Izabela Z and Murray, Eleanor and Bradley, Susan M and Hsu, Vernita and McGuire, Lisa and Schulz, Werner} } @article {359746, title = {Modifiable worker risk factors contributing to workplace absence: a stakeholder-centred best-evidence synthesis of systematic reviews.}, journal = {Work}, volume = {49}, number = {4}, year = {2014}, month = {2014}, pages = {541-58}, abstract = {BACKGROUND: A challenge facing stakeholders is the identification and translation of relevant high quality research to inform policy and practice. This study engaged academic and community stakeholders in conducting a best evidence-synthesis to identify modifiable risk and protective worker factors across health conditions impacting work-related absence. OBJECTIVES: To identify modifiable worker disability risk and protective factors across common health conditions impacting work-related absence. METHODS: We searched Medline, Embase, CINHAL, The Cochrane Library, PsycINFO, BusinessSourceComplete, and ABI/Inform from 2000 to 2011. Quantitative, qualitative, or mixed methods systematic reviews of work-focused population were considered for inclusion. Two or more reviewers independently reviewed articles for inclusion and methodological screening. RESULTS: The search strategy, expert input and grey literature identified 2,467 unique records. One hundred and forty-two full text articles underwent comprehensive review. Twenty-four systematic reviews met eligibility criteria. Modifiable worker factors found to have consistent evidence across two or more health conditions included emotional distress, negative enduring psychology/personality factors, negative health and disability perception, decreased physical activity, lack of family support, poor general health, increased functional disability, increased pain, increased fatigue and lack of motivation to return to work. CONCLUSIONS: Systematic reviews are limited by availability of high quality studies, lack of consistency of methodological screening and reporting, and variability of outcome measures used.}, issn = {1875-9270}, doi = {10.3233/WOR-131709}, author = {Wagner, Shannon and White, Marc and Schultz, Izabela and Murray, Eleanor and Bradley, Susan M and Hsu, Vernita and McGuire, Lisa and Schulz, Werner} } @article {astrakianakis2013conflicting, title = {Conflicting Effects of Occupational Endotoxin Exposure on Lung Health-A Hypothesis-Generating Review of Cancer and COPD Risk}, journal = {Journal of Environmental Immunology and Toxicology}, volume = {1}, year = {2013}, pages = {128{\textendash}139}, author = {Astrakianakis, George and Murray, Eleanor} } @article {359826, title = {Pain-related work interference is a key factor in a worker/workplace model of work absence duration due to musculoskeletal conditions in Canadian nurses.}, journal = {J Occup Rehabil}, volume = {23}, number = {4}, year = {2013}, month = {2013 Dec}, pages = {585-96}, abstract = {OBJECTIVE: To examine the role of pain experiences in relation to work absence, within the context of other worker health factors and workplace factors among Canadian nurses with work-related musculoskeletal (MSK) injury. METHODS: Structural equation modeling was used on a sample of 941 employed, female, direct care nurses with at least one day of work absence due to a work-related MSK injury, from the cross-sectional 2005 National Survey of the Work and Health of Nurses. RESULTS: The final model suggests that pain severity and pain-related work interference mediate the impact of the following worker health and workplace factors on work absence duration: depression, back problems, age, unionization, workplace physical demands and low job control. The model accounted for 14 \% of the variance in work absence duration and 46.6 \% of the variance in pain-related work interference. CONCLUSIONS: Our findings support a key role for pain severity and pain-related work interference in mediating the effects of workplace factors and worker health factors on work absence duration. Future interventions should explore reducing pain-related work interference through addressing workplace issues, such as providing modified work, reducing physical demands, and increasing job control.}, keywords = {Age Factors, Canada, Cross-Sectional Studies, Depression, Female, Humans, Labor Unions, Models, Theoretical, Musculoskeletal Pain, Nursing, Occupational Diseases, Professional Autonomy, Severity of Illness Index, Sick Leave, Time Factors, Workload, Workplace}, issn = {1573-3688}, doi = {10.1007/s10926-012-9408-7}, author = {Murray, Eleanor and Franche, Ren{\'e}e-Louise and Ibrahim, Selahadin and Smith, Peter and Carnide, Nancy and C{\^o}t{\'e}, Pierre and Gibson, Jane and Guzman, Jaime and Koehoorn, Mieke and Mustard, Cameron} } @article {359781, title = {Modifiable workplace risk factors contributing to workplace absence across health conditions: A stakeholder-centered best-evidence synthesis of systematic reviews.}, journal = {Work}, volume = {45}, number = {4}, year = {2013}, month = {2013}, pages = {475-92}, abstract = {BACKGROUND: A challenge facing stakeholders is the identification and translation of relevant high quality research to inform policy and practice. This study engaged academic and community stakeholders in conducting a best evidence-synthesis to enhance knowledge use. OBJECTIVES: To identify modifiable workplace disability risk and protective factors across common health conditions impacting work-related absence. METHODS: We searched MEDLINE, Embase, CINHAL, The Cochrane Library, PsycINFO, BusinessSourceComplete, and ABI/Inform from 2000 to 2011. Systematic reviews that employed quantitative, qualitative, or mixed methods of work-focused population were considered for inclusion. Two or more independent reviewers reviewed titles only, titles and abstracts, and/or full articles when assessing eligibility for inclusion. Selected articles underwent methodological screening. RESULTS: The search strategy, expert input and grey literature identified 2,467 unique records from which 142 full text articles underwent comprehensive review. Twenty-seven systematic reviews met eligibility criteria. Modifiable work factors found to have consistent evidence across two or more health conditions included lack of social support, increased physical demands at work, job strain, lack of supervisory support, increased psychological demands, low job satisfaction, low worker control of job, and poor leadership quality. CONCLUSIONS: The active engagement of stakeholders led to greater understanding of relevance of the study findings for community stakeholders and appreciation of the mutual benefits of collaboration.}, keywords = {Absenteeism, Evidence-Based Practice, Group Processes, Humans, Job Satisfaction, leadership, Occupational Health, Physical Exertion, Professional Autonomy, Risk Factors, Social Support, Workload, Workplace}, issn = {1875-9270}, doi = {10.3233/WOR-131628}, author = {White, Marc and Wagner, Shannon and Schultz, Izabela Z and Murray, Eleanor and Bradley, Susan M and Hsu, Vernita and McGuire, Lisa and Schulz, Werner} } @article {359871, title = {Workplace-based work disability prevention interventions for workers with common mental health conditions: a review of the literature.}, journal = {J Occup Rehabil}, volume = {22}, number = {2}, year = {2012}, month = {2012 Jun}, pages = {182-95}, abstract = {INTRODUCTION: To summarize evidence on workplace-based work disability prevention (WDP) interventions in workers with common mental health conditions (CMHCs). Primary outcomes of interest were work absence duration and work functioning; secondary outcomes were quality of life, and economic costs. METHODS: We conducted a systematic literature search in 5 electronic databases (MEDLINE, EMBASE, CINAHL, PsychINFO, Web of Science) for studies published from 2007 to 2009. Two reviewers screened for studies: (1) Targeting workers with CMHCs absent from, or struggling at, work; (2) evaluating workplace-based WDP interventions; (3) assessing our primary outcome(s); and (4) with controlled trials. Quality assessment (using 29 criteria) was performed by two reviewers. RESULTS: Our search yielded 671 abstracts: 8 eligible studies and of sufficient quality. We identified three main intervention elements: (a) Facilitation of access to clinical treatment; (b) Workplace-based high-intensity psychological intervention; and (c) Facilitation of navigation through the disability management system. Moderate evidence was found that facilitation of treatment improved work functioning, quality of life and economic outcomes, with limited evidence for work absence duration. Moderate evidence was found that psychological interventions, primarily cognitive-behavioral therapy, improved work functioning, quality of life, and economic outcomes. Moderate evidence indicated that facilitation of navigation through the disability management system improved work absence duration. CONCLUSIONS: Workplace-based interventions could improve work disability outcomes for workers with CMHCs. Facilitation of access to clinical treatment, and workplace-based high-intensity psychological intervention were most effective in improving work functioning and quality of life, and in reducing costs.}, keywords = {Absenteeism, Disabled Persons, Humans, Mental Disorders, Mental Health, Occupational Health, Occupational Health Services, Quality of Life, Social Support, Workplace}, issn = {1573-3688}, doi = {10.1007/s10926-011-9338-9}, author = {Pomaki, Georgia and Franche, Ren{\'e}e-Louise and Murray, Eleanor and Khushrushahi, Noushin and Lampinen, Thomas M} } @article {359921, title = {Examining the impact of worker and workplace factors on prolonged work absences among Canadian nurses.}, journal = {J Occup Environ Med}, volume = {53}, number = {8}, year = {2011}, month = {2011 Aug}, pages = {919-27}, abstract = {OBJECTIVE: To evaluate the impact of worker and workplace factors and of their relationships on work absence duration. METHODS: Structural equation modeling of 11,762 female, Canadian nurses from the 2005 National Survey of the Work and Health of Nurses. RESULTS: Worker and workplace factors were associated with prolonged work absence. Key proximal predictors were pain-related work interference, depression, pain severity, and respect and support at work. More distal predictors were multimorbidity, abuse at work, and organizational culture. CONCLUSIONS: Worker health and workplace factors are important in explaining work absence duration. Self-management for pain and mood, adapted to the work context, may be useful for nurses with chronic pain or depression. Policy makers and administrators should focus on creating respect and support at work, and improving organizational culture.}, keywords = {Absenteeism, Adult, Canada, Chronic Pain, Cross-Sectional Studies, Depression, Female, Humans, Middle Aged, Nurses, Organizational Culture, Self Care, Severity of Illness Index, Workplace}, issn = {1536-5948}, doi = {10.1097/JOM.0b013e3182255dea}, author = {Franche, Ren{\'e}e-Louise and Murray, Eleanor and Ibrahim, Selahadin and Smith, Peter and Carnide, Nancy and C{\^o}t{\'e}, Pierre and Gibson, Jane and Koehoorn, Mieke} } @article {359956, title = {Seasonal oscillation of human infection with influenza A/H5N1 in Egypt and Indonesia.}, journal = {PLoS One}, volume = {6}, number = {9}, year = {2011}, month = {2011}, pages = {e24042}, abstract = {As of June 22, 2011, influenza A/H5N1 has caused a reported 329 deaths and 562 cases in humans, typically attributed to contact with infected poultry. Influenza H5N1 has been described as seasonal. Although several studies have evaluated environmental risk factors for H5N1 in poultry, none have considered seasonality of H5N1 in humans. In addition, temperature and humidity are suspected to drive influenza in temperate regions, but drivers in the tropics are unknown, for H5N1 as well as other influenza viruses. An analysis was conducted to determine whether human H5N1 cases occur seasonally in association with changes in temperature, precipitation and humidity. Data analyzed were H5N1 human cases in Indonesia (nā€Š=ā€Š135) and Egypt (nā€Š=ā€Š50), from January 1, 2005 (Indonesia) or 2006 (Egypt) through May 1, 2008 obtained from WHO case reports, and average daily weather conditions obtained from NOAA{\textquoteright}s National Climatic Data Center. Fourier time series analysis was used to determine seasonality of cases and associations between weather conditions and human H5N1 incidence. Human H5N1 cases in Indonesia occurred with a period of 1.67 years/cycle (p, keywords = {Egypt, Fourier Analysis, Humans, Incidence, Indonesia, Influenza A Virus, H5N1 Subtype, Influenza, Human, Seasons, Time Factors, Weather}, issn = {1932-6203}, doi = {10.1371/journal.pone.0024042}, author = {Murray, Eleanor J and Morse, Stephen S} } @article {359981, title = {Work disability prevention in rural healthcare workers.}, journal = {Rural Remote Health}, volume = {10}, number = {4}, year = {2010}, month = {2010 Oct-Dec}, pages = {1502}, abstract = {INTRODUCTION: Approximately 20\% of healthcare workers in high-income countries such as Australia, Canada and the USA work in rural areas. Healthcare workers are known to be vulnerable to occupational injury and poor work disability outcomes; given their rural-urban distribution, it is possible to compare work disability prevention in rural and urban areas. However, little attention has been paid to work disability prevention issues specific to rural workers, including rural healthcare workers. A comprehensive review of the literature was conducted to identify rural-urban differences in work disability outcomes (defined as the incidence of occupational injury and the duration of associated work absence), as well as risk factors for poor work disability outcomes in rural healthcare workers. METHODS: The databases MEDLINE, CINAHL, and EMBASE were searched, as were relevant research centers and government agencies, to identify all quantitative and qualitative English-language studies published between 1 January 2000 and 6 October 2009 that discussed occupational injury, work absence duration, work disability management, or risk factors for poor work disability outcomes, for rural workers specifically, or in comparison with urban workers. To ensure inclusion of studies of healthcare workers as a distinct group among other sector-specific groups, a broad search for literature related to all industrial sectors was conducted. RESULTS: Of 860 references identified, 5 discussed work disability outcomes and 25 discussed known risk factors. Known risk factors were defined as factors firmly established to be associated with poor work disability outcomes in the general worker population based on systematic reviews, well-established conceptual models of work disability prevention, and public health literature. Although somewhat conflicting, the evidence suggests that rural healthcare workers experience higher rates of occupational injury compared with urban healthcare workers, within occupational categories. Rural workers also appear to be more vulnerable to prolonged work absence although the data are limited. No studies directly compared risk factors for work disability prevention outcomes between rural and urban healthcare workers. However, potential risk factors were identified at the level of the environment, worker, job, organization, worker compensation system and healthcare access. Important methodological limitations were noted, including unclear definitions of rurality, inadequate methods of urban-rural comparisons such as comparing samples from different countries, and a paucity of studies applying longitudinal or multivariate designs. CONCLUSIONS: There is a notable lack of evidence about work disability prevention issues for healthcare workers in rural areas. Available evidence supports the hypothesis that rural healthcare workers are vulnerable to occupational injury, and suggests they are vulnerable to prolonged work absence. They may be particularly vulnerable to poor work disability prevention outcomes due to complex patient needs in the context of risk factors such as heavy workloads, long hours, heavy on-call demands, high stress levels, limited support and workplace violence. Additional vulnerability may occur because their work conditions are managed in distant urban administrative centers, and due to barriers in their own healthcare access. Although rural healthcare workers seem generally at greater risk of injury, one study suggests that urban emergency medical service workers experience a high vulnerability to injury that may outweigh the effects of rurality. Additional research is needed to document rural-urban disparities in work disability outcomes and to identify associated sources and risk factors. Other issues to address are access to and quality of healthcare for rural healthcare workers, streamlining the compensation system, the unique needs of Aboriginal healthcare workers, and the management of prolonged work absence. Finally, occupational injury and work absence duration programs should be tailored to meet the needs of rural workers.}, keywords = {Accidents, Occupational, Databases, Bibliographic, Humans, Incidence, Risk Factors, Rural Health Services, Sick Leave, Urban Health Services, Wounds and Injuries}, issn = {1445-6354}, author = {Franche, Ren{\'e}e L and Murray, Eleanor J and Ostry, Aleck and Ratner, Pamela A and Wagner, Shannon L and Harder, Henry G} } @article {359941, title = {A rapid method for characterization of protein relatedness using feature vectors.}, journal = {PLoS One}, volume = {5}, number = {3}, year = {2010}, month = {2010}, pages = {e9550}, abstract = {We propose a feature vector approach to characterize the variation in large data sets of biological sequences. Each candidate sequence produces a single feature vector constructed with the number and location of amino acids or nucleic acids in the sequence. The feature vector characterizes the distance between the actual sequence and a model of a theoretical sequence based on the binomial and uniform distributions. This method is distinctive in that it does not rely on sequence alignment for determining protein relatedness, allowing the user to visualize the relationships within a set of proteins without making a priori assumptions about those proteins. We apply our method to two large families of proteins: protein kinase C, and globins, including hemoglobins and myoglobins. We interpret the high-dimensional feature vectors using principal components analysis and agglomerative hierarchical clustering. We find that the feature vector retains much of the information about the original sequence. By using principal component analysis to extract information from collections of feature vectors, we are able to quickly identify the nature of variation in a collection of proteins. Where collections are phylogenetically or functionally related, this is easily detected. Hierarchical agglomerative clustering provides a means of constructing cladograms from the feature vector output.}, keywords = {Algorithms, Cluster Analysis, Computational Biology, Databases, Protein, Glycine, Hemoglobins, Humans, Models, Statistical, Myoglobin, phylogeny, Principal Component Analysis, Protein Kinase C, Sequence Alignment, Software}, issn = {1932-6203}, doi = {10.1371/journal.pone.0009550}, author = {Carr, Kareem and Murray, Eleanor and Armah, Ebenezer and He, Rong L and Yau, Stephen S-T} } @article {359986, title = {Sp1 and Sp3 control constitutive expression of the human NHE2 promoter by interactions with the proximal promoter and the transcription initiation site.}, journal = {Biochem J}, volume = {407}, number = {1}, year = {2007}, month = {2007 Oct 1}, pages = {101-11}, abstract = {We have previously cloned the human Na+/H+ exchanger NHE2 gene and its promoter region. In the present study, the regulatory elements responsible for the constitutive expression of NHE2 were studied. Transient transfection assays revealed that the -40/+150 promoter region contains the core promoter responsible for the optimal promoter activity. A smaller fragment, -10/+40, containing the TIS (transcription initiation site) showed minimal activity. We identified a palindrome that overlaps the TIS and binds to the transcription factors Sp1 and Sp3. Mutations in the 5{\textquoteright} flank of the palindrome abolished the Sp1/Sp3 interaction and reduced promoter activity by approx. 45\%. In addition, a conserved GC-box centered at -25 was found to play a critical role in basal promoter activity and also interacted with Sp1 and Sp3. An internal deletion in the GC-box severely reduced the promoter activity. Sp1/Sp3 binding to these elements was established using gel-mobility shift assays, confirmed by chromatin immunoprecipitation and co-transfections in Drosophila SL2 cells. Furthermore, we identified two positive regulatory elements in the DNA region corresponding to the 5{\textquoteright}-UTR (5{\textquoteright}-untranslated region). The results in the present study indicate that Sp1 and Sp3 are required for constitutive NHE2 expression and that the positive regulatory elements of the 5{\textquoteright}-UTR may co-operate with the 5{\textquoteright}-flanking region to achieve the optimal promoter activity.}, keywords = {5{\textquoteright} Untranslated Regions, Animals, Binding Sites, Cells, Cultured, CpG Islands, Drosophila, Humans, Mutation, Promoter Regions, Genetic, Regulatory Elements, Transcriptional, Sodium-Hydrogen Antiporter, Sp1 Transcription Factor, Sp3 Transcription Factor, Transcription Initiation Site}, issn = {1470-8728}, doi = {10.1042/BJ20070364}, author = {Pearse, Ian and Zhu, Ying X and Murray, Eleanor J and Dudeja, Pradeep K and Ramaswamy, Krishnamurthy and Malakooti, Jaleh} }