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1.  G-Computation Demonstration in Causal Mediation Analysis 
European journal of epidemiology  2015;30(10):1119-1127.
Recent work has considerably advanced the definition, identification and estimation of controlled direct, and natural direct and indirect effects in causal mediation analysis. Despite the various estimation methods and statistical routines being developed, a unified approach for effect estimation under different effect decomposition scenarios is still needed for epidemiologic research. G-computation offers such unification and has been used for total effect and joint controlled direct effect estimation settings, involving different types of exposure and outcome variables. In this study, we demonstrate the utility of parametric g-computation in estimating various components of the total effect, including (i) natural direct and indirect effects, (ii) standard and stochastic controlled direct effects, and (iii) reference and mediated interaction effects, using Monte Carlo simulations in standard statistical software. For each study subject, we estimated their nested potential outcomes corresponding to the (mediated) effects of an intervention on the exposure wherein the mediator was allowed to attain the value it would have under a possible counterfactual exposure intervention, under a pre-specified distribution of the mediator independent of any causes, or under a fixed controlled value. A final regression of the potential outcome on the exposure intervention variable was used to compute point estimates and bootstrap was used to obtain confidence intervals. Through contrasting different potential outcomes, this analytical framework provides an intuitive way of estimating effects under the recently introduced 3- and 4- way effect decomposition. This framework can be extended to complex multivariable and longitudinal mediation settings.
doi:10.1007/s10654-015-0100-z
PMCID: PMC4674449  PMID: 26537707
g-computation; parametric g-formula; mediation analysis; effect decomposition; simulation
2.  Association of Incident Obstructive Sleep Apnea with Outcomes in a Large Cohort of US Veterans 
Thorax  2015;70(9):888-895.
Rationale
There is a paucity of large cohort studies examining the association of obstructive sleep apnea(OSA) with clinical outcomes including all-cause mortality, coronary heart disease(CHD), strokes and chronic kidney disease(CKD).
Objectives
We hypothesized that a diagnosis of incident OSA is associated with higher risks of these adverse clinical outcomes.
Methods, Measurements
In a nationally representative cohort of over 3 million(n=3,079,514) US veterans(93% male) with baseline estimated glomerular filtration rate (eGFR)≥60 ml/min/1.73m2, we examined the association between the diagnosis of incident OSA, treated and untreated with continuous positive airway pressure(CPAP), and: 1) all-cause mortality, 2) incident CHD, 3) incident strokes, 4)incident CKD defined as eGFR<60 ml/min/1.73m2, and 5)slopes of eGFR.
Main Results
Compared to OSA negative patients, untreated and treated OSA was associated with 86% higher mortality risk,(adjusted hazard ratio and 95% confidence interval: 1.86(1.81-1.91)) and 35% (1.35(1.21-1.51)), respectively. Similarly, untreated and treated OSA was associated with 3.5 times(3.54(3.40-3.69)) and 3 times(3.06(2.62-3.56)) higher risk of incident CHD; 3.5 times higher risk of incident strokes(3.48(3.28-3.64) and 3.50(2.92-4.19)) for untreated and treated OSA, respectively. The risk of incident CKD was also significantly higher in untreated(2.27(2.19-2.36)) and treated(2.79(2.48-3.13)) OSA patients. The median (interquartile range) of the eGFR slope was −0.41(−2.01 - 0.99), −0.61(−2.69 - 0.93) and −0.87(−3.00 - 0.70)ml/min/1.73m2 in OSA negative, untreated and treated OSA positive patients, respectively.
Conclusions
In this large and contemporary cohort of more than 3 million US veterans, a diagnosis of incident OSA was associated with higher mortality, incident CHD, stroke and CKD and with faster kidney function decline.
doi:10.1136/thoraxjnl-2015-206970
PMCID: PMC4575815  PMID: 26038534
coronary heart disease; chronic kidney disease; continuous positive airway pressure; kidney function; mortality; obstructive sleep apnea; stroke
3.  Predictors of treatment with dialysis modalities in observational studies for comparative effectiveness research* 
Nephrology Dialysis Transplantation  2015;30(7):1208-1217.
Background
The Institute of Medicine has identified the comparative effectiveness of renal replacement therapies as a kidney-related topic among the top 100 national priorities. Given the importance of ensuring internal and external validity, the goal of this study was to identify potential sources of bias in observational studies that compare outcomes with different dialysis modalities.
Methods
This observational cohort study used data from the electronic medical records of all patients that started maintenance dialysis in the calendar years 2007–2011 and underwent treatment for at least 60 days in any of the 2217 facilities operated by DaVita Inc. Each patient was assigned one of six dialysis modalities for each 91-day period from the date of first dialysis (thrice weekly in-center hemodialysis (HD), peritoneal dialysis (PD), less-frequent HD, home HD, frequent HD and nocturnal in-center HD).
Results
Of the 162 644 patients, 18% underwent treatment with a modality other than HD for at least one 91-day period. Except for PD, patients started treatment with alternative modalities after variable lengths of treatment with HD; the time until a change in modality was shortest for less-frequent HD (median time = 6 months) and longest for frequent HD (median time = 15 months). Between 30 and 78% of patients transferred to another dialysis facility prior to change in modality. Finally, there were significant differences in baseline and time-varying clinical characteristics associated with dialysis modality.
Conclusions
This analysis identified numerous potential sources of bias in studies of the comparative effectiveness of dialysis modalities.
doi:10.1093/ndt/gfv097
PMCID: PMC4560036  PMID: 25883196
bias; comparative effectiveness research; end-stage renal disease; hemodialysis; peritoneal dialysis
4.  Erythropoietin Dose and Mortality in Hemodialysis Patients: Marginal Structural Model to Examine Causality 
It has been previously reported that a higher erythropoiesis stimulating agent (ESA) dose in hemodialysis patients is associated with adverse outcomes including mortality; however the causal relationship between ESA and mortality is still hotly debated. We hypothesize ESA dose indeed exhibits a direct linear relationship with mortality in models of association implementing the use of a marginal structural model (MSM), which controls for time-varying confounding and examines causality in the ESA dose-mortality relationship. We conducted a retrospective cohort study of 128 598 adult hemodialysis patients over a 5-year follow-up period to evaluate the association between weekly ESA (epoetin-α) dose and mortality risk. A MSM was used to account for baseline and time-varying covariates especially laboratory measures including hemoglobin level and markers of malnutrition-inflammation status. There was a dose-dependent positive association between weekly epoetin-α doses ≥18 000 U/week and mortality risk. Compared to ESA dose of <6 000 U/week, adjusted odds ratios (95% confidence interval) were 1.02 (0.94–1.10), 1.08 (1.00–1.18), 1.17 (1.06–1.28), 1.27 (1.15–1.41), and 1.52 (1.37–1.69) for ESA dose of 6 000 to <12 000, 12 000 to <18 000, 18 000 to <24 000, 24 000 to <30 000, and ≥30 000 U/week, respectively. High ESA dose may be causally associated with excessive mortality, which is supportive of guidelines which advocate for conservative management of ESA dosing regimen in hemodialysis patients.
doi:10.1155/2016/6087134
PMCID: PMC4889858  PMID: 27298736
5.  Bias from conditioning on live birth in pregnancy cohorts: an illustration based on neurodevelopment in children after prenatal exposure to organic pollutants 
Only 60–70% of fertilized eggs may result in a live birth, and very early fetal loss mainly goes unnoticed. Outcomes that can only be ascertained in live-born children will be missing for those who do not survive till birth. In this article, we illustrate a common bias structure (leading to ‘live-birth bias’) that arises from studying the effects of prenatal exposure to environmental factors on long-term health outcomes among live births only in pregnancy cohorts. To illustrate this we used prenatal exposure to perfluoroalkyl substances (PFAS) and attention-deficit/hyperactivity disorder (ADHD) in school-aged children as an example. PFAS are persistent organic pollutants that may impact human fecundity and be toxic for neurodevelopment. We simulated several hypothetical scenarios based on characteristics from the Danish National Birth Cohort and found that a weak inverse association may appear even if PFAS do not cause ADHD but have a considerable effect on fetal survival. The magnitude of the negative bias was generally small, and adjusting for common causes of the outcome and fetal loss can reduce the bias. Our example highlights the need to identify the determinants of pregnancy loss and the importance of quantifying bias arising from conditioning on live birth in observational studies.
doi:10.1093/ije/dyu249
PMCID: PMC4339763  PMID: 25604449
Bias analysis; live-birth bias; reproductive epidemiology; birth cohort; prenatal exposure; perfluoroalkyl substances; attention-deficit/hyperactivity disorder
6.  Associations between self-perception of weight, food choice intentions, and consumer response to calorie information: a retrospective investigation of public health center clients in Los Angeles County before the implementation of menu-labeling regulation 
BMC Public Health  2016;16:60.
Background
Although obesity continues to rise and remains a great public health concern in the U.S., a number of important levers such as self-perception of weight and calorie postings at point-of-purchase in restaurants are still not well-characterized in the literature, especially for low-income and minority groups in Los Angeles County (LAC). To study this gap, we examined the associations of self-perception of weight (as measured by body weight discrepancy) with food choice intentions and consumer response to calorie information among low-income adults residing in LAC during the pre-menu labeling regulation era.
Methods
Descriptive and multivariable logistic regression analyses were performed to examine the aforementioned associations utilizing data from the 2007–2008 Calorie and Nutrition Information Survey (CNIS). The CNIS was a local health department study of 639 low-income adults recruited from five large, multi-purpose public health centers in LAC.
Results
Survey participants who reported that their desired weight was less than their current weight (versus desired weight the same as current weight) had (i) higher odds of intending to select lower-calorie foods under the scenario that calorie information was available at point-of-purchase (aOR = 2.0; 95 % CI: 1.0–3.9); and (ii) had higher odds of reporting that it is “very important” to have these calorie postings on food items in grocery stores (aOR = 3.1; 95 % CI: 0.90–10.7) and in fast-food restaurants (aOR = 3.4; 95 % CI: 1.0–11.4).
Conclusions
Self-perception of weight was found to be associated with the intention to select lower-calorie foods under the scenario that calorie information was available at point-of-purchase. Future public health efforts to support menu labeling implementation should consider these and other findings to inform consumer education and communications strategies that can be tailored to assist restaurant patrons with this forthcoming federal law.
Electronic supplementary material
The online version of this article (doi:10.1186/s12889-016-2714-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12889-016-2714-9
PMCID: PMC4722675  PMID: 26801241
Calorie information; Menu labeling; Obesity; Food choice; Self-perceived weight
7.  Focus on Quality: Investigating Residents’ Learning Climate Perceptions 
PLoS ONE  2016;11(1):e0147108.
Background
A department’s learning climate is known to contribute to the quality of postgraduate medical education and, as such, to the quality of patient care provided by residents. However, it is unclear how the learning climate is perceived over time.
Objectives
This study investigated whether the learning climate perceptions of residents changed over time.
Methods
The context for this study was residency training in the Netherlands. Between January 2012 and December 2014, residents from 223 training programs in 39 hospitals filled out the web-based Dutch Residency Educational Climate Test (D-RECT) to evaluate their clinical department’s learning climate. Residents had to fill out 35 validated questions using a five point Likert-scale. We analyzed data using generalized linear mixed (growth) models.
Results
Overall, 3982 D-RECT evaluations were available to investigate our aim. The overall mean D-RECT score was 3.9 (SD = 0.3). The growth model showed an increase in D-RECT scores over time (b = 0.03; 95% CI: 0.01–0.06; p < 0.05).
Conclusions
The observed increase in D-RECT scores implied that residents perceived an improvement in the learning climate over time. Future research could focus on factors that facilitate or hinder learning climate improvement, and investigate the roles that hospital governing committees play in safeguarding and improving the learning climate.
doi:10.1371/journal.pone.0147108
PMCID: PMC4713097  PMID: 26765742
8.  Time series analysis of maternal mortality in Africa from 1990 to 2005 
Objectives
Most global maternal deaths occur in Africa and Asia. In response, the Millennium Development Goal (MDG-5) calls for a 75% reduction in maternal mortality from 1990 to 2015. To assess the potential for progress in MDG-5 in Africa, we examined the cross-sectional and longitudinal associations of socioeconomic, demographic and population-health factors with maternal mortality rates in Africa.
Methods
We used data from global agencies and the published literature to identify socioeconomic, demographic and population-health explanatory factors that could be correlated with maternal mortality in 49 countries of Africa for the years 1990, 1995, 2000 and 2005. We used correlation, negative binomial and mixed Poisson regression models to investigate whether there exist associations between potential explanatory factors and maternal mortality.
Results
Some African countries have made substantial progress towards achieving MDG-5 while others have fallen behind. Lower gross domestic product (GDP) and female enrolment in primary schools, but higher HIV prevalence, neonatal mortality rate and total fertility rate, were associated with higher maternal mortality.
Conclusions
Maternal mortality rates in African countries appear to be declining. The mean maternal mortality ratios in Africa decreased from 695.82 in 1990 to 562.18 in 2005. Yet some countries are more likely than others to achieve MDG-5. Better socioeconomic, demographic and population health development appear to be conducive to better maternal health in Africa. Sustained efforts on all these fronts will be needed to close the gap in maternal survival and achieve MDG-5 in Africa.
doi:10.1136/jech-2013-202565
PMCID: PMC4689199  PMID: 23851148
9.  Mortality Benefits of Antibiotic Computerised Decision Support System: Modifying Effects of Age 
Scientific Reports  2015;5:17346.
Antibiotic computerised decision support systems (CDSSs) are shown to improve antibiotic prescribing, but evidence of beneficial patient outcomes is limited. We conducted a prospective cohort study in a 1500-bed tertiary-care hospital in Singapore, to evaluate the effectiveness of the hospital’s antibiotic CDSS on patients’ clinical outcomes, and the modification of these effects by patient factors. To account for clustering, we used multilevel logistic regression models. One-quarter of 1886 eligible inpatients received CDSS-recommended antibiotics. Receipt of antibiotics according to CDSS’s recommendations seemed to halve mortality risk of patients (OR 0.54, 95% CI 0.26–1.10, P = 0.09). Patients aged ≤65 years had greater mortality benefit (OR 0.45, 95% CI 0.20–1.00, P = 0.05) than patients that were older than 65 (OR 1.28, 95% CI 0.91–1.82, P = 0.16). No effect was observed on incidence of Clostridium difficile (OR 1.02, 95% CI 0.34–3.01), and multidrug-resistant organism (OR 1.06, 95% CI 0.42–2.71) infections. No increase in infection-related readmission (OR 1.16, 95% CI 0.48–2.79) was found in survivors. Receipt of CDSS-recommended antibiotics reduced mortality risk in patients aged 65 years or younger and did not increase the risk in older patients. Physicians should be informed of the benefits to increase their acceptance of CDSS recommendations.
doi:10.1038/srep17346
PMCID: PMC4663624  PMID: 26617195
10.  Implementation of Departmental Quality Strategies Is Positively Associated with Clinical Practice: Results of a Multicenter Study in 73 Hospitals in 7 European Countries 
PLoS ONE  2015;10(11):e0141157.
Background
Given the amount of time and resources invested in implementing quality programs in hospitals, few studies have investigated their clinical impact and what strategies could be recommended to enhance its effectiveness.
Objective
To assess variations in clinical practice and explore associations with hospital- and department-level quality management systems.
Design
Multicenter, multilevel cross-sectional study.
Setting and Participants
Seventy-three acute care hospitals with 276 departments managing acute myocardial infarction, deliveries, hip fracture, and stroke in seven countries.
Intervention
None.
Measures
Predictor variables included 3 hospital- and 4 department-level quality measures. Six measures were collected through direct observation by an external surveyor and one was assessed through a questionnaire completed by hospital quality managers. Dependent variables included 24 clinical practice indicators based on case note reviews covering the 4 conditions (acute myocardial infarction, deliveries, hip fracture and stroke). A directed acyclic graph was used to encode relationships between predictors, outcomes, and covariates and to guide the choice of covariates to control for confounding.
Results and Limitations
Data were provided on 9021 clinical records by 276 departments in 73 hospitals. There were substantial variations in compliance with the 24 clinical practice indicators. Weak associations were observed between hospital quality systems and 4 of the 24 indicators, but on analyzing department-level quality systems, strong associations were observed for 8 of the 11 indicators for acute myocardial infarction and stroke. Clinical indicators supported by higher levels of evidence were more frequently associated with quality systems and activities.
Conclusions
There are significant gaps between recommended standards of care and clinical practice in a large sample of hospitals. Implementation of department-level quality strategies was significantly associated with good clinical practice. Further research should aim to develop clinically relevant quality standards for hospital departments, which appear to be more effective than generic hospital-wide quality systems.
doi:10.1371/journal.pone.0141157
PMCID: PMC4654525  PMID: 26588842
11.  Parkinson disease and smoking revisited 
Neurology  2014;83(16):1396-1402.
Objective:
To assess whether being able to quit smoking is an early marker of Parkinson disease (PD) onset rather than tobacco being “neuroprotective,” we analyzed information about ease of quitting and nicotine substitute use.
Methods:
For this case-control study, we identified 1,808 patients with PD diagnosed between 1996 and 2009 from Danish registries, matched 1,876 population controls on sex and year of birth, and collected lifestyle information. We estimated odds ratios and 95% confidence intervals with logistic regression adjusting for matching factors and confounders.
Results:
Fewer patients with PD than controls ever established a smoking habit. Among former smokers, those with greater difficulty quitting or using nicotine substitutes were less likely to develop PD, with the risk being lowest among those reporting “extremely difficult to quit” compared with “easy to quit.” Nicotine substitute usage was strongly associated with quitting difficulty and duration of smoking, i.e., most strongly among current smokers, followed by former smokers who had used nicotine substitutes, and less strongly among former smokers who never used substitutes.
Conclusions:
Our data support the notion that patients with PD are able to quit smoking more easily than controls. These findings are compatible with a decreased responsiveness to nicotine during the prodromal phase of PD. We propose that ease of smoking cessation is an aspect of premanifest PD similar to olfactory dysfunction, REM sleep disorders, or constipation and suggests that the apparent “neuroprotective” effect of smoking observed in epidemiologic studies is due to reverse causation.
doi:10.1212/WNL.0000000000000879
PMCID: PMC4206154  PMID: 25217056
12.  SELECTION BIAS MODELING USING OBSERVED DATA AUGMENTED WITH IMPUTED RECORD-LEVEL PROBABILITIES 
Annals of epidemiology  2014;24(10):747-753.
PURPOSE
Selection bias is a form of systematic error that can be severe in compromised study designs such as case-control studies with inappropriate selection mechanisms or follow-up studies that suffer from extensive attrition. External adjustment for selection bias is commonly undertaken when such bias is suspected, but the methods used can be overly simplistic, if not unrealistic, and fail to allow for simultaneous adjustment of associations of the exposure and covariates with the outcome, when of interest. Internal adjustment for selection bias via inverse-probability-weighting allows bias parameters to vary with levels of covariates but has only been formalized for longitudinal studies with covariate data on patients up until loss-to-follow-up.
METHODS
We demonstrate the use of inverse-probability-weighting and externally obtained bias parameters to perform internal adjustment of selection bias in studies lacking covariate data on unobserved participants.
RESULTS
The ‘true’ or selection-adjusted odds ratio for the association between exposure and outcome was successfully obtained by analyzing only data on those in the selected stratum (i.e. responders) weighted by the inverse probability of their being selected as function of their observed covariate data.
CONCLUSIONS
This internal adjustment technique using user-supplied bias parameters and inverse-probability-weighting for selection bias can be applied to any type of observational study.
doi:10.1016/j.annepidem.2014.07.014
PMCID: PMC4259547  PMID: 25175700
Epidemiologic methods; selection bias; casual inference
13.  Patterns and Predictors of Early Mortality in Incident Hemodialysis Patients: New Insights 
American journal of nephrology  2012;35(6):548-558.
Background
Incident hemodialysis patients have the highest mortality in the first several months after starting dialysis treatments. We hypothesized that the pattern and risk factors associated with this early mortality differ from those in later dialysis therapy periods.
Methods
We examined mortality patterns and predictors during the first several months of hemodialysis treatment in 18,707 incident patients since the first week of hemodialysis therapy and estimated the population attributable fractions for selected time periods in the first 24 months.
Results
The 18,707 incident hemodialysis patients were 45% women and 54% diabetics. The standardized mortality ratio (95% confidence interval) in the 1st to 3rd month of hemodialysis therapy were 1.81 (1.74-1.88), 1.79 (1.72-1.86), and 1.34 (1.27-1.40), respectively. SMR reached prevalent mortality only by 7th month. No survival advantage for African Americans existed in the first 6 months. Patients with low albumin <3.5 g/dL had the highest proportion of infection-related deaths while patients with higher albumin levels had higher CV deaths including76% of death during the first 3 months. Use of catheter as vascular access and hypoalbuminemia <3.5 g/dL explained 34% (17%-54%) and 33% (19%-45%) of all deaths in the first 90 days, respectively.
Conclusions
Incident hemodialysis patients have the highest mortality during the first 6 months including 80% higher death risk in the first 2 months. Presence of catheter and hypoalbuminemia<3.5 g/dL each explains 1/3 of all deaths in the first 90 days.
doi:10.1159/000338673
PMCID: PMC4587354  PMID: 22677686
Incident hemodialysis patients; mortality predictor; population attributable fraction
15.  Patient Experience Shows Little Relationship with Hospital Quality Management Strategies 
PLoS ONE  2015;10(7):e0131805.
Objectives
Patient-reported experience measures are increasingly being used to routinely monitor the quality of care. With the increasing attention on such measures, hospital managers seek ways to systematically improve patient experience across hospital departments, in particular where outcomes are used for public reporting or reimbursement. However, it is currently unclear whether hospitals with more mature quality management systems or stronger focus on patient involvement and patient-centered care strategies perform better on patient-reported experience. We assessed the effect of such strategies on a range of patient-reported experience measures.
Materials and Methods
We employed a cross-sectional, multi-level study design randomly recruiting hospitals from the Czech Republic, France, Germany, Poland, Portugal, Spain, and Turkey between May 2011 and January 2012. Each hospital contributed patient level data for four conditions/pathways: acute myocardial infarction, stroke, hip fracture and deliveries. The outcome variables in this study were a set of patient-reported experience measures including a generic 6-item measure of patient experience (NORPEQ), a 3-item measure of patient-perceived discharge preparation (Health Care Transition Measure) and two single item measures of perceived involvement in care and hospital recommendation. Predictor variables included three hospital management strategies: maturity of the hospital quality management system, patient involvement in quality management functions and patient-centered care strategies. We used directed acyclic graphs to detail and guide the modeling of the complex relationships between predictor variables and outcome variables, and fitted multivariable linear mixed models with random intercept by hospital, and adjusted for fixed effects at the country level, hospital level and patient level.
Results
Overall, 74 hospitals and 276 hospital departments contributed data on 6,536 patients to this study (acute myocardial infarction n = 1,379, hip fracture n = 1,503, deliveries n = 2,088, stroke n = 1,566). Patients admitted for hip fracture and stroke had the lowest scores across the four patient-reported experience measures throughout. Patients admitted after acute myocardial infarction reported highest scores on patient experience and hospital recommendation; women after delivery reported highest scores for patient involvement and health care transition. We found no substantial associations between hospital-wide quality management strategies, patient involvement in quality management, or patient-centered care strategies with any of the patient-reported experience measures.
Conclusion
This is the largest study so far to assess the complex relationship between quality management strategies and patient experience with care. Our findings suggest absence of and wide variations in the institutionalization of strategies to engage patients in quality management, or implement strategies to improve patient-centeredness of care. Seemingly counterintuitive inverse associations could be capturing a scenario where hospitals with poorer quality management were beginning to improve their patient experience. The former suggests that patient-centered care is not yet sufficiently integrated in quality management, while the latter warrants a nuanced assessment of the motivation and impact of involving patients in the design and assessment of services.
doi:10.1371/journal.pone.0131805
PMCID: PMC4494712  PMID: 26151864
16.  Autism Spectrum Disorders and Race, Ethnicity, and Nativity: A Population-Based Study 
Pediatrics  2014;134(1):e63-e71.
OBJECTIVE:
Our understanding of the influence of maternal race/ethnicity and nativity and childhood autistic disorder (AD) in African Americans/blacks, Asians, and Hispanics in the United States is limited. Phenotypic differences in the presentation of childhood AD in minority groups may indicate etiologic heterogeneity or different thresholds for diagnosis. We investigated whether the risk of developing AD and AD phenotypes differed according to maternal race/ethnicity and nativity.
METHODS:
Children born in Los Angeles County with a primary AD diagnosis at ages 3 to 5 years during 1998–2009 were identified and linked to 1995–2006 California birth certificates (7540 children with AD from a cohort of 1 626 354 births). We identified a subgroup of children with AD and a secondary diagnosis of mental retardation and investigated heterogeneity in language and behavior.
RESULTS:
We found increased risks of being diagnosed with AD overall and specifically with comorbid mental retardation in children of foreign-born mothers who were black, Central/South American, Filipino, and Vietnamese, as well as among US-born Hispanic and African American/black mothers, compared with US-born whites. Children of US African American/black and foreign-born black, foreign-born Central/South American, and US-born Hispanic mothers were at higher risk of exhibiting an AD phenotype with both severe emotional outbursts and impaired expressive language than children of US-born whites.
CONCLUSIONS:
Maternal race/ethnicity and nativity are associated with offspring’s AD diagnosis and severity. Future studies need to examine factors related to nativity and migration that may play a role in the etiology as well as identification and diagnosis of AD in children.
doi:10.1542/peds.2013-3928
PMCID: PMC4067639  PMID: 24958588
autistic disorder; emigration and immigration; epidemiology; continental population groups
17.  Dose of Hemodialysis and Survival: A Marginal Structural Model Analysis 
American journal of nephrology  2014;39(5):383-391.
Background
Observational studies have consistently demonstrated the survival benefits of greater dialysis dose in maintenance hemodialysis (MHD) patients, whereas randomized controlled trials have shown conflicting results. The possible causal impact of dialysis dose on mortality needs to be investigated using rich cohort data analyzed with novel statistical methods such as marginal structural models (MSM) that account for time-varying confounding and exposure.
Methods
We quantified the effect of delivered dose of hemodialysis (single-pool Kt/V [spKt/V]) on mortality risk in a contemporary cohort of 68,110 patients undergoing thrice-weekly hemodialysis (7/2001-9/2005). We compared conventional Cox proportional hazard and MSM survival analyses, accounting for time-varying confounding by applying longitudinally modeled inverse-probability-of-dialysis-dose weights to each observation.
Results
In conventional Cox models, baseline spKt/V showed a weak negative association with mortality, while higher time-averaged spKt/V was strongly associated with lower mortality risk. In MSM analyses, compared to a spKt/V range of 1.2–<1.4, a spKt/V range of <1.2 was associated with a higher risk of mortality (HR [95% CI] 1.67 [1.55–1.81]), whereas mortality risks were significantly lower with higher spKt/V [HRs (95%CI): 0.74(0.70–0.78), 0.63(0.59–0.66), 0.56(0.52–0.60), and 0.56(0.52–0.61) for spKt/V ranges of 1.4–<1.6, 1.6–<1.8, 1.8–<2.0, and ≥2.0, respectively]. Thus, MSM analyses showed that the greatest survival advantage of higher dialysis dose was observed for a spKt/V range of 1.8–<2.0, and the dialysis dose-mortality relationship was robust in almost all subgroups of patients.
Conclusions
Higher doses of hemodialysis were robustly associated with greater survival in MSM analyses that more fully and appropriately accounted for time-varying confounding.
doi:10.1159/000362285
PMCID: PMC4048641  PMID: 24776927
hemodialysis dose; hemodialysis adequacy; mortality; survival; marginal structural model
18.  A Systematic Review of the Impact of Physicians’ Occupational Well-Being on the Quality of Patient Care 
Background
It is widely held that the occupational well-being of physicians may affect the quality of their patient care. Yet, there is still no comprehensive synthesis of the evidence on this connection.
Purpose
This systematic review studied the effect of physicians’ occupational well-being on the quality of patient care.
Methods
We systematically searched PubMed, Embase, and PsychINFO from inception until August 2014. Two authors independently reviewed the studies. Empirical studies that explored the association between physicians’ occupational well-being and patient care quality were considered eligible. Data were systematically extracted on study design, participants, measurements, and findings. The Medical Education Research Study Quality Instrument (MERSQI) was used to assess study quality.
Results
Ultimately, 18 studies were included. Most studies employed an observational design and were of average quality. Most studies reported positive associations of occupational well-being with patient satisfaction, patient adherence to treatment, and interpersonal aspects of patient care. Studies reported conflicting findings for occupational well-being in relation to technical aspects of patient care. One study found no association between occupational well-being and patient health outcomes.
Conclusions
The association between physicians’ occupational well-being and health care’s ultimate goal—improved patient health—remains understudied. Nonetheless, research up till date indicated that physicians’ occupational well-being can contribute to better patient satisfaction and interpersonal aspects of care. These insights may help in shaping the policies on physicians’ well-being and quality of care.
Electronic supplementary material
The online version of this article (doi:10.1007/s12529-015-9473-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s12529-015-9473-3
PMCID: PMC4642595  PMID: 25733349
Occupational well-being; Job satisfaction; Physicians; Quality of patient care; Patient satisfaction
19.  Administered Paricalcitol Dose and Survival in Hemodialysis Patients: A Marginal Structural Model Analysis 
Pharmacoepidemiology and drug safety  2012;21(11):1232-1239.
Purpose
Several observational studies have indicated that vitamin D receptor activators (VDRA), including paricalcitol, are associated with greater survival in maintenance hemodialysis (MHD) patients. However, patients with higher serum parathyroid hormone (PTH), a surrogate of higher death risk, are usually given higher VDRA doses, which can lead to confounding by indication and attenuate the expected survival advantage of high VDRA doses.
Methods
We examined mortality-predictability of low (>1 but <10 μg/week) versus high (≥10 μg/week) dose of administered paricalcitol over time in a contemporary cohort of 15,442 MHD patients (age 64±15 years, 55% men, 44% diabetes, 35% African Americans) from all DaVita dialysis clinics across the USA (7/2001-6/2006 with survival follow-ups until 6/2007) using conventional Cox regression, propensity score (PS) matching, and marginal structural model (MSM) analyses.
Results
In our conventional Cox models and PS matching models, low dose of paricalcitol was not associated with mortality either in baseline (hazard ratio (HR): 1.03, 95%confidence interval (CI): (0.97-1.09)) and (HR: 0.99, 95%CI: (0.86-1.14)) or time-dependent (HR: 1.04, 95%CI: (0.98-1.10)) and (HR: 1.12, 95%CI: (0.98-1.28)) models, respectively. In contrast, compared to high dose of paricalcitol, low dose was associated with a 26% higher risk of mortality (HR: 1.26, 95%CI: (1.19-1.35)) in MSM. The association between dose of paricalcitol and mortality was robust in almost all subgroups of patients using MSMs.
Conclusions
Higher dose of paricalcitol appears causally associated with greater survival in MHD patients. Randomized controlled trials need to verify the survival effect of paricalcitol dose in maintenance hemodialysis patients are indicated.
doi:10.1002/pds.3349
PMCID: PMC4304639  PMID: 22996597
Mortality; propensity score; marginal structural model; mineral and bone disorders; chronic kidney disease; paricalcitol
20.  Nutritional predictors of early mortality in incident hemodialysis patients 
Purpose
Low serum albumin concentration and low dietary protein intake are associated with protein-energy wasting (PEW) and higher mortality in maintenance hemodialysis patients. The role of these nutritional markers is less clear in clinical outcomes of the first several months of dialysis therapy, where mortality is exceptionally high.
Methods
In a cohort of 17,445 incident hemodialysis patients, we examined variation in serum albumin and the normalized protein catabolic rate (nPCR), a surrogate of dietary intake, and quarterly mortality in the first 2 years of dialysis therapy. Cox proportional hazard models were fitted to estimate the association between mortality and combined albumin/nPCR categories for eight quarters. We investigated the associations between mortality and baseline and subsequent serum albumin levels per cohort quarter as well as changes in albumin and nPCR over time.
Results
Patients were 64 ± 15 years old (mean ± SD) and included 45 % women, 24 % African Americans and 58 % diabetics. Correlations between quarterly serum albumin and nPCR varied from 0.18 to 0.25. Serum albumin <3.5 g/dL was consistently associated with high mortality as was nPCR <1 g/kg/day (except for qtr1). Low serum albumin and nPCR greater than 0.2 g/dLg/dL or g/kg/day, respectively, were associated with increased risk of death. Quarterly rise in nPCR (>+0.2 g/kg/day) showed reverse effect on mortality from the 2nd to the last quarter.
Conclusions
Low serum albumin and nPCR are associated with mortality. A rapid rise in nPCR by the end of the second year may indicate pre-existing PEW.
doi:10.1007/s11255-013-0459-2
PMCID: PMC3870190  PMID: 23703546
Hemodialysis; Mortality; Albumin; Protein catabolic rate
21.  Body Mass Index and Poor Self-Rated Health in 49 Low-Income and Middle-Income Countries, By Sex, 2002–2004 
This study investigated whether the relationship between body mass index (BMI) and poor self-rated health differed by sex in low-income countries and middle-income countries. We analyzed data from the World Health Survey (2002–2004) on 160,099 participants from 49 low-income and middle-income countries by using random-intercept multilevel logistic regressions. We found a U-shaped relationship between BMI and poor self-rated health among both sexes in both low-income and middle-income countries, but the relationship differed by sex in strength and direction between low-income countries and middle-income countries. Differential perception of body weight and general health might explain some of the observed sex differences.
doi:10.5888/pcd12.150070
PMCID: PMC4556100  PMID: 26292064
22.  COMPETING RISK BIAS TO EXPLAIN THE INVERSE RELATIONSHIP BETWEEN SMOKING AND MALIGNANT MELANOMA 
European journal of epidemiology  2013;28(7):10.1007/s10654-013-9812-0.
The relationship between smoking and melanoma remains unclear. Among the different results is the paradoxical finding that smoking was shown to be inversely associated with the risk of malignant melanoma in some large cohort and case-control studies, even after control for suspected confounding variables. Smoking is a known risk factor for many non-communicable diseases, including coronary heart disease, stroke, as well as other malignancies; it has been shown to be positively associated with other types of skin cancer, and there remains no clear biologic explanation for a possible protective effect on malignant melanoma. In this paper, we propose a plausible mechanism of bias from smoking-related competing risks that may explain or contribute to the inverse association between smoking and melanoma as spurious. Using directed acyclic graphs for formalization and visualization of assumptions, and Monte Carlo simulation techniques, we demonstrate how published inverse associations might be compatible with selection bias resulting from uncontrolled or unmeasured common causes of competing outcomes of smoking-related diseases and malignant melanoma. We present results from various scenarios assuming a true null as well as a true positive association between smoking and malignant melanoma. Under a true null assumption, we find inverse associations due to the biasing mechanism to be compatible with published results in the literature, especially after the addition of unmeasured confounding variables. This study could be seen as offering a cautionary note in the interpretation of published smoking-melanoma findings.
doi:10.1007/s10654-013-9812-0
PMCID: PMC3864891  PMID: 23700026
Bias (Epidemiology); Melanoma; Smoking
23.  Measuring Professionalism in Medicine and Nursing: Results of a European Survey 
PLoS ONE  2014;9(5):e97069.
Background
Leveraging professionalism has been put forward as a strategy to drive improvement of patient care. We investigate professionalism as a factor influencing the uptake of quality improvement activities by physicians and nurses working in European hospitals.
Objective
To (i) investigate the reliability and validity of data yielded by using the self-developed professionalism measurement tool for physicians and nurses, (ii) describe their levels of professionalism displayed, and (iii) quantify the extent to which professional attitudes would predict professional behaviors.
Methods and Materials
We designed and deployed survey instruments amongst 5920 physicians and nurses working in European hospitals. This was conducted under the cross-sectional multilevel study “Deepening Our Understanding of Quality Improvement in Europe” (DUQuE). We used psychometric and generalized linear mixed modelling techniques to address the aforementioned objectives.
Results
In all, 2067 (response rate 69.8%) physicians and 2805 nurses (94.8%) representing 74 hospitals in 7 European countries participated. The professionalism instrument revealed five subscales of professional attitude and one scale for professional behaviour with moderate to high internal consistency and reliability. Physicians and nurses display equally high professional attitude sum scores (11.8 and 11.9 respectively out of 16) but seem to have different perceptions towards separate professionalism aspects. Lastly, professionals displaying higher levels of professional attitudes were more involved in quality improvement actions (physicians: b = 0.019, P<0.0001; nurses: b = 0.016, P<0.0001) and more inclined to report colleagues’ underperformance (physicians – odds ratio (OR) 1.12, 95% CI 1.01–1.24; nurses – OR 1.11, 95% CI 1.01–1.23) or medical errors (physicians – OR 1.14, 95% CI 1.01–1.23; nurses – OR 1.43, 95% CI 1.22–1.67). Involvement in QI actions was found to increase the odds of reporting incompetence or medical errors.
Conclusion
A tool that reliably and validly measures European physicians’ and nurses’ commitment to professionalism is now available. Collectively leveraging professionalism as a quality improvement strategy may be beneficial to patient care quality.
doi:10.1371/journal.pone.0097069
PMCID: PMC4029578  PMID: 24849320
24.  Personality Traits Affect Teaching Performance of Attending Physicians: Results of a Multi-Center Observational Study 
PLoS ONE  2014;9(5):e98107.
Background
Worldwide, attending physicians train residents to become competent providers of patient care. To assess adequate training, attending physicians are increasingly evaluated on their teaching performance. Research suggests that personality traits affect teaching performance, consistent with studied effects of personality traits on job performance and academic performance in medicine. However, up till date, research in clinical teaching practice did not use quantitative methods and did not account for specialty differences. We empirically studied the relationship of attending physicians' personality traits with their teaching performance across surgical and non-surgical specialties.
Method
We conducted a survey across surgical and non-surgical specialties in eighteen medical centers in the Netherlands. Residents evaluated attending physicians' overall teaching performance, as well as the specific domains learning climate, professional attitude, communication, evaluation, and feedback, using the validated 21-item System for Evaluation of Teaching Qualities (SETQ). Attending physicians self-evaluated their personality traits on a 5-point scale using the validated 10-item Big Five Inventory (BFI), yielding the Five Factor model: extraversion, conscientiousness, neuroticism, agreeableness and openness.
Results
Overall, 622 (77%) attending physicians and 549 (68%) residents participated. Extraversion positively related to overall teaching performance (regression coefficient, B: 0.05, 95% CI: 0.01 to 0.10, P = 0.02). Openness was negatively associated with scores on feedback for surgical specialties only (B: −0.10, 95% CI: −0.15 to −0.05, P<0.001) and conscientiousness was positively related to evaluation of residents for non-surgical specialties only (B: 0.13, 95% CI: 0.03 to 0.22, p = 0.01).
Conclusions
Extraverted attending physicians were consistently evaluated as better supervisors. Surgical attending physicians who display high levels of openness were evaluated as less adequate feedback-givers. Non-surgical attending physicians who were conscientious seem to be good at evaluating residents. These insights could contribute to future work on development paths of attending physicians in medical education.
doi:10.1371/journal.pone.0098107
PMCID: PMC4028262  PMID: 24844725
25.  Cell Phone Exposures and Hearing Loss in Children in the Danish National Birth Cohort 
Background
Children today are exposed to cell phones early in life, and may be the most vulnerable if exposure is harmful to health. We investigated the association between cell phone use and hearing loss in children.
Methods
The Danish National Birth Cohort (DNBC) enrolled pregnant women between 1996 and 2002. Detailed interviews were conducted during gestation, and when the children were 6 months, 18 months, and 7 years of age. We used multivariable-adjusted logistic regression, marginal structural models (MSM) with inverse-probability weighting, and doubly-robust estimation (DRE) to relate hearing loss at age 18 months to cell phone use at age seven years, and to investigate cell phone use reported at age seven in relation to hearing loss at age seven.
Results
Our analyses included data from 52,680 children. We observed weak associations between cell phone use and hearing loss at age seven, with odds ratios and 95% confidence intervals from the traditional logistic regression, MSM, and DRE models being 1.21 [0.99–1.46], 1.23 [1.01–1.49], and 1.22 [1.00–1.49], respectively.
Conclusions
Our findings could have been affected by various biases and are not sufficient to conclude that cell phone exposures have an effect on hearing. This is the first large-scale epidemiologic study to investigate this potentially important association among children, and replication of these findings is needed.
doi:10.1111/ppe.12036
PMCID: PMC3625978  PMID: 23574412

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