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1.  Testing for baseline differences in randomized controlled trials: an unhealthy research behavior that is hard to eradicate 
According to the CONSORT statement, significance testing of baseline differences in randomized controlled trials should not be performed. In fact, this practice has been discouraged by numerous authors throughout the last forty years. During that time span, reporting of baseline differences has substantially decreased in the leading general medical journals. Our own experience in the field of nutrition behavior research however, is that co-authors, reviewers and even editors are still very persistent in their demand for these tests. The aim of this paper is therefore to negate this demand by providing clear evidence as to why testing for baseline differences between intervention groups statistically is superfluous and why such results should not be published.
Testing for baseline differences is often propagated because of the belief that it shows whether randomization was successful and it identifies real or important differences between treatment arms that should be accounted for in the statistical analyses. Especially the latter argument is flawed, because it ignores the fact that the prognostic strength of a variable is also important when the interest is in adjustment for confounding. In addition, including prognostic variables as covariates can increase the precision of the effect estimate. This means that choosing covariates based on significance tests for baseline differences might lead to omissions of important covariates and, less importantly, to inclusion of irrelevant covariates in the analysis. We used data from four supermarket trials on the effects of pricing strategies on fruit and vegetables purchases, to show that results from fully adjusted analyses sometimes do appreciably differ from results from analyses adjusted for significant baseline differences only. We propose to adjust for known or anticipated important prognostic variables. These could or should be pre-specified in trial protocols. Subsequently, authors should report results from the fully adjusted as well as crude analyses, especially for dichotomous and time to event data.
Based on our arguments, which were illustrated by our findings, we propose that journals in and outside the field of nutrition behavior actively adopt the CONSORT 2010 statement on this topic by not publishing significance tests for baseline differences anymore.
PMCID: PMC4310023  PMID: 25616598
Epidemiology; Methods; Reporting; Nutrition behavior research; Statistical analyses
2.  Effectiveness of a Worksite Social & Physical Environment Intervention on Need for Recovery, Physical Activity and Relaxation; Results of a Randomized Controlled Trial 
PLoS ONE  2014;9(12):e114860.
To investigate the effectiveness of a worksite social and physical environment intervention on need for recovery (i.e., early symptoms of work-related mental and physical fatigue), physical activity and relaxation. Also, the effectiveness of the separate interventions was investigated.
In this 2×2 factorial design study, 412 office employees from a financial service provider participated. Participants were allocated to the combined social and physical intervention, to the social intervention only, to the physical intervention only or to the control group. The primary outcome measure was need for recovery. Secondary outcomes were work-related stress (i.e., exhaustion, detachment and relaxation), small breaks, physical activity (i.e., stair climbing, active commuting, sport activities, light/moderate/vigorous physical activity) and sedentary behavior. Outcomes were measured by questionnaires at baseline, 6 and 12 months follow-up. Multilevel analyses were performed to investigate the effects of the three interventions.
In all intervention groups, a non-significant reduction was found in need for recovery. In the combined intervention (n = 92), exhaustion and vigorous physical activities decreased significantly, and small breaks at work and active commuting increased significantly compared to the control group. The social intervention (n = 118) showed a significant reduction in exhaustion, sedentary behavior at work and a significant increase in small breaks at work and leisure activities. In the physical intervention (n = 96), stair climbing at work and active commuting significantly increased, and sedentary behavior at work decreased significantly compared to the control group.
None of the interventions was effective in improving the need for recovery. It is recommended to implement the social and physical intervention among a population with higher baseline values of need for recovery. Furthermore, the intervention itself could be improved by increasing the intensity of the intervention (for example weekly GMI-sessions), providing physical activity opportunities and exercise schemes, and by more drastic environment interventions (restructuring entire department floor).
Trial Registration
Nederlands Trial Register NTR2553
PMCID: PMC4277283  PMID: 25542039
3.  Number and appraisal of daily hassles and life events in young adulthood: the association with physical activity and screen time: a longitudinal cohort study 
BMC Public Health  2014;14(1):1067.
Young adults face radical life changes regarding residence, marriage, family and work that may negatively impact their health behaviours. Therefore, we investigated the associations of the number of daily hassles and life events and their subjective appraisal with physical activity and screen time in young adulthood.
Data came from participants of the Amsterdam Growth and Health Longitudinal Study (AGAHLS). Self-reported physical activity (min/wk) was used from wave 6 (1991; mean age 27), wave 7 (1993; mean age 29), wave 8 (1996/1997; mean age 32) and 9 (2000; mean age 36). Self-reported screen time (h/wk) was assessed in waves 8 and 9. The number and the appraisal of daily hassles and major life events were assessed with the Everyday Problem Checklist and Life Events List, respectively (including five life event domains, i.e.: health, work, home/family, personal/social relations, and finances). The final sample included 474 participants for the physical activity analyses and 475 participants for the screen time analyses. To test the longitudinal associations of daily hassles and life events with physical activity and screen time, univariable and multivariable Generalised Estimating Equations were performed. Effect modification by gender was tested.
Physical activity levels were higher in those who had experienced more daily hassles. People who reported higher subjective appraisal in the work and finances life event domains also had higher levels of physical activity, although only the subjective appraisal in the finances domain remained significant in the multivariable model. No significant associations between number and subjective appraisal of daily hassles and life events and screen time were observed.
The occurrence of specific life events may be more influential for people’s physical activity behaviour than their respective sum or emotional tone. Still, the assessment of daily hassles may be a relevant addition in this research field. Finally, we suggest that daily hassles and life events are less important for explaining screen time behaviour than for physical activity.
PMCID: PMC4213509  PMID: 25308800
Adults; GEE; Prospective cohort; Sedentary behaviour
4.  The Association between IGF-1 Polymorphisms, IGF-1 Serum Levels, and Cognitive Functions in Healthy Adults: The Amsterdam Growth and Health Longitudinal Study 
Several studies have demonstrated an association between polymorphisms in the insulin-like growth factor-1 (IGF-1) gene and IGF-1 serum levels. IGF-1 levels have been associated with cognitive functioning in older persons and growth hormone deficient patients. The present study investigates whether IGF-1 polymorphisms, IGF-1 levels, and cognition are interconnected in healthy adults. Data of 277 participants (mean age: 42.4 years) of the Amsterdam Growth and Health Longitudinal Study on IGF-1 promoter polymorphisms, IGF-1 serum level, spatial working memory (SWM), paired associate learning (PAL), and IQ tests were analyzed. (M)ANOVAs were applied to confirm the associations between IGF-1 polymorphisms and IGF-1 levels and between IGF-1 levels and cognition. Three groups were distinguished based on specific IGF-1 polymorphism alleles: a homozygote 192 bp/192 bp genotype, a heterozygote 192 bp/x genotype, and a noncarrier x/x genotype. Although different IGF-1 levels were found for the three genotypes, performance on all cognitive tasks and IQ measures was similar. Despite the associations between IGF-1 polymorphisms and IGF-1 levels, no association was found between cognition and IGF-1 levels. It seems that IGF-1 does not play a role in the cognitive performance of healthy middle-aged adults. Possible, IGF-1 fulfills a more developmental and protective role in cognition which becomes apparent during childhood, old-age, or disease.
PMCID: PMC4120488  PMID: 25114679
5.  Long-Term Results of a Web-Based Guided Self-Help Intervention for Employees With Depressive Symptoms: Randomized Controlled Trial 
Depressive disorders are highly prevalent in the working population and are associated with excessive costs. The evidence for effective worker-directed interventions for employees with depressive symptoms is limited. Treating employees with depressive symptoms via the Internet before they report sick from work could be beneficial and cost saving.
In this study, we tested the effectiveness over the period of 1 year of a Web-based guided self-help intervention, called Happy@Work, for employees with depressive symptoms who were not on sick leave.
A two-arm randomized controlled trial comparing a worker-directed, Web-based, guided self-help intervention to care as usual (CAU) was carried out. We recruited employees from 6 companies via the company’s Intranet and by putting up posters. The inclusion criteria were elevated depressive symptoms as measured by a score ≥16 on the Center for Epidemiologic Studies Depression scale (CES-D) and not being on sick leave. The intervention contained 6 lessons and consisted of problem-solving treatment and cognitive therapy. Participants were asked to submit weekly assignments via the website after completion of a lesson and they received feedback from a coach via the website. Self-report questionnaires on depressive symptoms (CES-D; primary outcome), burnout (Maslach Burnout Inventory, MBI), work performance (Health and Work Performance Questionnaire, HPQ), duration of absenteeism, and anxiety (Hospital Anxiety and Depression Scale, HADS; secondary outcomes), were completed at baseline, posttreatment, and at 6-, and 12-month follow-up. Several subgroup and per-protocol analyses were performed.
A total of 231 employees were randomized to either the intervention group (n=116) or to CAU (n=115). Completion of assessments varied between 54%-74%. Improvement in depressive symptoms between baseline and posttreatment was shown in all participants and these effects sustained over time. However, there were no differences between the 2 groups (adjusted regression coefficient=0.46, 95% CI –2.11 to 3.03, P=.72; Cohen’s d=0.05). Differences between groups were also not significant for the secondary outcomes. No subgroups were identified to show differences between the groups, nor did we find a between-group effect in the per-protocol analyses.
This study showed that a worker-directed, Web-based, guided self-help intervention was not more effective than CAU in reducing depressive symptoms among employees with depressive symptoms who were not on sick leave over the period of 1 year. An intervention for this specific target group might not be necessary because the recovery in the CAU group was comparable to the intervention group and sustained over a 12-month period.
Trial Registration
Nederlands Trial Register (NTR): NTR2993; (Archived by WebCite at
PMCID: PMC4115257  PMID: 25008127
depression; employees; occupational intervention; self-help; prevention; burnout; Internet
6.  Self-management abilities and frailty are important for healthy aging among community-dwelling older people; a cross-sectional study 
BMC Geriatrics  2014;14:28.
This study aimed to identify the relationships of self-management abilities and frailty to perceived poor health among community-dwelling older people in the Netherlands while controlling for important individual characteristics such as education, age, marital status, and gender.
The cross-sectional study sample consisted of 869/2212 (39% response rate) independently living older adults (aged ≥70 years) in 92 neighborhoods of Rotterdam. In the questionnaires we assessed self-rated health, frailty using the Tilburg Frailty Indicator (TFI) and self-management abilities with the short version of the Self-Management Ability Scale (SMAS-S). We first used descriptive analysis to identify those in poor and good health. Differences between groups were established using chi-squared and t-tests. Relationships between individual characteristics, frailty, self-management abilities and poor health were investigated with correlation analyses. Multilevel logistic regression analyses were than performed to investigate the relationships of self-management abilities and frailty to health while controlling for age, gender, education, and marital status. The results of the multilevel regression analyses are reported as odd ratios.
Respondents in poor health were older than those in good health (78.8 vs. 77.2; p ≤ .001). A significantly larger proportion of older people in poor health were poorly educated (38.4% vs. 19.0%; p ≤ .001) and fewer were married (33.6% vs. 46.3%; p ≤ .001). Furthermore, older people in poor health reported significantly lower self-management abilities (3.5 vs. 4.1; p ≤ .001) and higher levels of frailty (6.9 vs. 3.3; p ≤ .001). Correlation analyses showed significant relationships between frailty, self-management abilities and poor health. Multilevel analyses showed that, after controlling for background characteristics, self-management abilities were negatively associated with poor health (p ≤ .05) and a positive relationship was found between frailty and poor health (p ≤ .05) among older people in the community.
Self-management abilities and frailty are important for healthy aging among community-dwelling older people in the Netherlands. Particularly vulnerable are the lower educated older adults. Interventions to improve self-management abilities may help older people age healthfully and prevent losses as they age further.
PMCID: PMC3975729  PMID: 24602327
Community study; Netherlands; Self-management; Frailty; Health
7.  A Healthy Brain in a Healthy Body: Brain Network Correlates of Physical and Mental Fitness 
PLoS ONE  2014;9(2):e88202.
A healthy lifestyle is an important focus in today's society. The physical benefits of regular exercise are abundantly clear, but physical fitness is also associated with better cognitive performance. How these two factors together relate to characteristics of the brain is still incompletely understood. By applying mathematical concepts from ‘network theory’, insights in the organization and dynamics of brain functioning can be obtained. We test the hypothesis that neural network organization mediates the association between cardio respiratory fitness (i.e. VO2 max) and cognitive functioning. A healthy cohort was studied (n = 219, 113 women, age range 41–44 years). Subjects underwent resting-state eyes-closed magneto-encephalography (MEG). Five artifact-free epochs were analyzed and averaged in six frequency bands (delta-gamma). The phase lag index (PLI) was used as a measure of functional connectivity between all sensors. Modularity analysis was performed, and both within and between-module connectivity of each sensor was calculated. Subjects underwent a maximum oxygen uptake (VO2 max) measurement as an indicator of cardio respiratory fitness. All subjects were tested with a commonly used Dutch intelligence test. Intelligence quotient (IQ) was related to VO2 max. In addition, VO2 max was negatively associated with upper alpha and beta band modularity. Particularly increased intermodular connectivity in the beta band was associated with higher VO2 max and IQ, further indicating a benefit of more global network integration as opposed to local connections. Within-module connectivity showed a spatially varied pattern of correlation, while average connectivity did not show significant results. Mediation analysis was not significant. The occurrence of less modularity in the resting-state is associated with better cardio respiratory fitness, while having increased intermodular connectivity, as opposed to within-module connections, is related to better physical and mental fitness.
PMCID: PMC3912221  PMID: 24498438
8.  Biological, socio-demographic, work and lifestyle determinants of sitting in young adult women: a prospective cohort study 
Sitting is associated with health risks. Factors that influence sitting are however not well understood. The aim was to examine the biological, socio-demographic, work-related and lifestyle determinants of sitting time (including during transport, work and leisure) in young adult Australian women.
Self-reported data from 11,676 participants (aged 22–27 years in 2000) in the Australian Longitudinal Study on Women’s Health were collected over 9 years in 2000, 2003, 2006 and 2009. Generalised Estimating Equations were used to examine univariable and multivariable associations of body mass index (BMI), country of birth, area of residence, education, marital status, number of children, occupational status, working hours, physical activity, smoking, alcohol intake and stress with week- and weekend-day sitting time.
Compared with women in the respective referent categories, (1) women with higher BMI, those born in Asia, those with less than University level education, doing white collar work, working 41–48 hours a week, current smokers, non, rare or risky/high risk drinkers and those being somewhat stressed had significantly higher sitting time; and (2) women living in rural and remote areas, partnered women, those with children, those without a paid job and blue collar workers, those working less than 34 hours a week, and active women had significantly lower sitting time.
Among young adult Australian women, those with higher BMI, those born in Asia, those with higher level occupations and long working hours, were most at risk of higher sitting time. These results can be used to identify at-risk groups and inform intervention development.
PMCID: PMC3904408  PMID: 24457004
Epidemiology; Prospective studies; Sedentary lifestyle; Women’s health
9.  Birth setting, transfer and maternal sense of control: results from the DELIVER study 
In the Netherlands, low risk women receive midwife-led care and can choose to give birth at home or in hospital. There is concern that transfer of care during labour from midwife-led care to an obstetrician-led unit leads to negative birth experiences, in particular among those with planned home birth. In this study we compared sense of control, which is a major attribute of the childbirth experience, for women planning home compared to women planning hospital birth under midwife-led care. In particular, we studied sense of control among women who were transferred to obstetric-led care during labour according to planned place of birth: home versus hospital.
We used data from the prospective multicentre DELIVER (Data EersteLIjns VERloskunde) cohort-study, conducted in 2009 and 2010 in the Netherlands. Sense of control during labour was assessed 6 weeks after birth, using the short version of the Labour Agentry Scale (LAS-11). A higher LAS-11 score indicates a higher feeling of control. We considered a difference of a minimum of 5.5 points as clinically relevant.
Nulliparous- and parous women who planned a home birth had a 2.6 (95% CI 1.0, 4.3) and a 3.0 (1.6, 4.4) higher LAS score during first stage of labour respectively and during second stage a higher score of 2.8 (0.9, 4.7) and 2.3 (0.6, 4.0), compared with women who planned a hospital birth. Overall, women who were transferred experienced a lower sense of control than women who were not transferred. Parous women who planned a home birth and who were transferred had a 4.3 (0.2, 8.4) higher LAS score in 2nd stage, compared to those who planned a hospital birth and who were transferred.
We found no clinically relevant differences in feelings of control among women who planned a home or hospital birth. Transfer of care during labour lowered feelings of control, but feelings of control were similar for transferred women who planned a home or hospital birth.
As far as their expected sense of control is concerned, low risk women should be encouraged to give birth at the location of their preference.
PMCID: PMC3898490  PMID: 24438469
10.  Increased risk for chronic comorbid disorders in patients with inflammatory arthritis: a population based study 
BMC Family Practice  2013;14:199.
Studies determining the development of a wide variety of different comorbid disorders in inflammatory arthritis (IA) patients are scarce, however, this knowledge could be helpful in optimising preventive care in IA patients. The aim of this study is to establish the risk that new chronic comorbid disorders in newly diagnosed patients with IA in a primary care setting are developed.
This is a nested-case–control study from 2001–2010 using data from electronic medical patient records in general practice. In total, 3,354 patients with newly diagnosed IA were selected. Each patient was matched with two control patients of the same age and sex in the same general practice. The development of 121 chronic comorbid disorders of index and control patients was compared using Cox regression.
After a median follow-up period of 2.8 years, 56% of the IA-patients had developed at least one chronic comorbid disorder after the onset of IA, compared to 46% of the control patients (p < 0.05). The most frequent developed comorbid disorders after the onset of IA were of cardiovascular (23%), and musculoskeletal (17%) origin. The highest hazard ratios (HRs) were found for anaemia (HR 2.0 [95% CI: 1.4-2.7]) osteoporosis (HR 1.9 [1.4-2.4]), and COPD (HR 1.8 [1.4-2.3]).
Patients with IA developed more chronic comorbid disorders after the onset of IA than one might expect based on age and sex. Since comorbidity has a large impact on the disease course, quality of life, and possibly on treatment itself, prevention of comorbidity should be one of the main targets in the treatment of IA patients.
PMCID: PMC3909051  PMID: 24364915
Inflammatory arthritis; Comorbidity; General practice; Disease onset; Chronic disease
11.  Stop Antibiotics on guidance of Procalcitonin Study (SAPS): a randomised prospective multicenter investigator-initiated trial to analyse whether daily measurements of procalcitonin versus a standard-of-care approach can safely shorten antibiotic duration in intensive care unit patients - calculated sample size: 1816 patients 
BMC Infectious Diseases  2013;13:178.
Unnecessary long-term use of broad-spectrum antibiotics is linked to the emergence and selection of resistant bacteria, prolonged hospitalisation and increased costs. Several clinical trials indicate that the biomarker procalcitonin (PCT) can guide antibiotic therapy. Some of these trials have shown a promising reduction in the number of antibiotic prescriptions, duration of antibiotic therapy and even length of stay in the ICU, although their size and selection criteria limit their external validity. The objectives of the Stop Antibiotics on guidance of Procalcitonin Study (SAPS) are to evaluate whether daily PCT can improve “real-life” antibiotic use in Dutch ICU’s by reduction of the duration of antibiotic treatment without an increase of recurrent infections and mortality.
Multicenter randomised controlled intervention trial. Powered for superiority of the primary efficacy endpoint and non-inferiority on the primary safety endpoints (non-inferiority margin is set on 8%).
Inclusion criteria: (1) ICU-patients aged ≥18 years and (2) receiving antibiotics for a presumed or proven infection and (3) signed informed consent. Exclusion criteria: (1) patients who require prolonged antibiotic therapy, (2) suffer from Mycobacterium tuberculosis, (3) cystic fibrosis, (4) viral or parasitic infections and (5) those that are severely immunocompromised or (6) moribund.
The intervention consists solely of an advice to discontinue antibiotic treatment in case PCT has decreased by more than 80% of its peak level (relative stopping threshold) or decrease below a value of 0.5 ng/ml (absolute stopping threshold).
The study hypothesis is that PCT-guided therapy is non-inferior to standard care based on implemented guidelines and local expertise, whilst reducing antibiotic usage. Computerised 1:1 randomisation will allocate 908 patients per arm. Arm 1: standard of care. Arm 2: procalcitonin-guided therapy. The primary efficacy endpoint is consumption of antibiotics expressed as the defined daily dosage and duration of antibiotic therapy expressed in days of therapy. This trial is designed to shorten antibiotics safely, therefore the primary safety endpoint is mortality measured at 28 day and 1 year.
This will be the largest procalcitonin-guided antibiotic intervention trial in ICU setting thus far. Currently 1600 of the planned 1816 patients are randomised (November 2012). The first interim analysis has passed without any safety or futility issues.
Trial registration
Trial registration number at Id. Nr. NCT01139489 , at NTR1861.
PMCID: PMC3637799  PMID: 23590389
Antibiotics; Antibiotic duration; Biomarker; Critical illness; C-reactive protein; Defined daily dosage; Intensive care unit; Procalcitonin; Sepsis; Septic shock
12.  Resting-state functional connectivity as a marker of disease progression in Parkinson's disease: A longitudinal MEG study☆ 
NeuroImage : Clinical  2013;2:612-619.
The assessment of resting-state functional connectivity has become an important tool in studying brain disease mechanisms. Here we use magnetoencephalography to longitudinally evaluate functional connectivity changes in relation to clinical measures of disease progression in Parkinson's disease (PD).
Using a source-space based approach with detailed anatomical mapping, functional connectivity was assessed for temporal, prefrontal and high order sensory association areas known to show neuropathological changes in early clinical disease stages.
At baseline, early stage, untreated PD patients (n = 12) had lower parahippocampal and temporal delta band connectivity and higher temporal alpha1 band connectivity compared to controls. Longitudinal analyses over a 4-year period in a larger patient group (n = 43) revealed decreases in alpha1 and alpha2 band connectivity for multiple seed regions that were associated with motor or cognitive deterioration.
In the earliest clinical stages of PD, delta and alpha1 band resting-state functional connectivity is altered in temporal cortical regions. With disease progression, a reversal of the initial changes in alpha1 and additional decreases in alpha2 band connectivity evolving in a more widespread cortical pattern. These changes in functional connectivity appear to reflect clinically relevant phenomena and therefore hold promise as a marker of disease progression, with potential predictive value for clinical outcome.
•We use MEG to longitudinally evaluate resting-state functional connectivity in PD.•We report alterations in delta and alpha1 band connectivity in early-stage PD.•These changes evolve over the disease course in relation to clinical deterioration.•Connectivity changes hold promise as a marker of disease progression in PD.•They may also have potential predictive value for clinical outcome.
PMCID: PMC3777670  PMID: 24179812
Parkinson's disease; Functional connectivity; Cognitive decline; Magnetoencephalography (MEG); Longitudinal
13.  A new approach to analyse longitudinal epidemiological data with an excess of zeros 
Within longitudinal epidemiological research, ‘count’ outcome variables with an excess of zeros frequently occur. Although these outcomes are frequently analysed with a linear mixed model, or a Poisson mixed model, a two-part mixed model would be better in analysing outcome variables with an excess of zeros. Therefore, objective of this paper was to introduce the relatively ‘new’ method of two-part joint regression modelling in longitudinal data analysis for outcome variables with an excess of zeros, and to compare the performance of this method to current approaches.
Within an observational longitudinal dataset, we compared three techniques; two ‘standard’ approaches (a linear mixed model, and a Poisson mixed model), and a two-part joint mixed model (a binomial/Poisson mixed distribution model), including random intercepts and random slopes. Model fit indicators, and differences between predicted and observed values were used for comparisons. The analyses were performed with STATA using the GLLAMM procedure.
Regarding the random intercept models, the two-part joint mixed model (binomial/Poisson) performed best. Adding random slopes for time to the models changed the sign of the regression coefficient for both the Poisson mixed model and the two-part joint mixed model (binomial/Poisson) and resulted into a much better fit.
This paper showed that a two-part joint mixed model is a more appropriate method to analyse longitudinal data with an excess of zeros compared to a linear mixed model and a Poisson mixed model. However, in a model with random slopes for time a Poisson mixed model also performed remarkably well.
PMCID: PMC3599839  PMID: 23425202
Two-part joint model; Excess of zeros; Count; Mixed modelling; Longitudinal; Statistical methods
14.  Prediction models for clustered data: comparison of a random intercept and standard regression model 
When study data are clustered, standard regression analysis is considered inappropriate and analytical techniques for clustered data need to be used. For prediction research in which the interest of predictor effects is on the patient level, random effect regression models are probably preferred over standard regression analysis. It is well known that the random effect parameter estimates and the standard logistic regression parameter estimates are different. Here, we compared random effect and standard logistic regression models for their ability to provide accurate predictions.
Using an empirical study on 1642 surgical patients at risk of postoperative nausea and vomiting, who were treated by one of 19 anesthesiologists (clusters), we developed prognostic models either with standard or random intercept logistic regression. External validity of these models was assessed in new patients from other anesthesiologists. We supported our results with simulation studies using intra-class correlation coefficients (ICC) of 5%, 15%, or 30%. Standard performance measures and measures adapted for the clustered data structure were estimated.
The model developed with random effect analysis showed better discrimination than the standard approach, if the cluster effects were used for risk prediction (standard c-index of 0.69 versus 0.66). In the external validation set, both models showed similar discrimination (standard c-index 0.68 versus 0.67). The simulation study confirmed these results. For datasets with a high ICC (≥15%), model calibration was only adequate in external subjects, if the used performance measure assumed the same data structure as the model development method: standard calibration measures showed good calibration for the standard developed model, calibration measures adapting the clustered data structure showed good calibration for the prediction model with random intercept.
The models with random intercept discriminate better than the standard model only if the cluster effect is used for predictions. The prediction model with random intercept had good calibration within clusters.
PMCID: PMC3658967  PMID: 23414436
Logistic regression analysis; Prediction model with random intercept; Validation
15.  External validation of two prediction models identifying employees at risk of high sickness absence: cohort study with 1-year follow-up 
BMC Public Health  2013;13:105.
Two models including age, self-rated health (SRH) and prior sickness absence (SA) were found to predict high SA in health care workers. The present study externally validated these prediction models in a population of office workers and investigated the effect of adding gender as a predictor.
SRH was assessed at baseline in a convenience sample of office workers. Age, gender and prior SA were retrieved from an occupational health service register. Two pre-defined prediction models were externally validated: a model identifying employees with high (i.e. ≥30) SA days and a model identifying employees with high (i.e. ≥3) SA episodes during 1-year follow-up. Calibration was investigated by plotting the predicted and observed probabilities and calculating the calibration slope. Discrimination was examined by receiver operating characteristic (ROC) analysis and the area under the ROC-curve (AUC).
A total of 593 office workers had complete data and were eligible for analysis. Although the SA days model showed acceptable calibration (slope = 0.89), it poorly discriminated office workers with high SA days from those without high SA days (AUC = 0.65; 95% CI 0.58–0.71). The SA episodes model showed acceptable discrimination (AUC = 0.76, 95% CI 0.70–0.82) and calibration (slope = 0.96). The prognostic performance of the prediction models did not improve in the population of office workers after adding gender.
The SA episodes model accurately predicted the risk of high SA episodes in office workers, but needs further multisite validation and requires a simpler presentation format before it can be used to select high-risk employees for interventions to prevent or reduce SA.
PMCID: PMC3599809  PMID: 23379546
Absenteeism; Forecasting; Generalization; Office workers; Regression prognostics; Sick leave; Transportability
16.  Improving the application of a practice guideline for the assessment and treatment of suicidal behavior by training the full staff of psychiatric departments via an e-learning supported Train-the-Trainer program: study protocol for a randomized controlled trial 
Trials  2013;14:9.
In 2012, in The Netherlands a multidisciplinary practice guideline for the assessment and treatment of suicidal behavior was issued. The release of guidelines often fails to change professional behavior due to multiple barriers. Structured implementation may improve adherence to guidelines. This article describes the design of a study measuring the effect of an e-learning supported Train-the-Trainer program aiming at the training of the full staff of departments in the application of the guideline. We hypothesize that both professionals and departments will benefit from the program.
In a multicenter cluster randomized controlled trial, 43 psychiatric departments spread over 10 regional mental health institutions throughout The Netherlands will be clustered in pairs with respect to the most prevalent diagnostic category of patients and average duration of treatment. Pair members are randomly allocated to either the experimental or the control condition. In the experimental condition, the full staff of departments, that is, all registered nurses, psychologists, physicians and psychiatrists (n = 532, 21 departments) will be trained in the application of the guideline, in a one-day small interactive group Train-the-Trainer program. The program is supported by a 60-minute e-learning module with video vignettes of suicidal patients and additional instruction. In the control condition (22 departments, 404 professionals), the guideline shall be disseminated in the traditional way: through manuals, books, conferences, internet, reviews and so on. The effectiveness of the program will be assessed at the level of both health care professionals and departments.
We aim to demonstrate the effect of training of the full staff of departments with an e-learning supported Train-the-Trainer program in the application of a new clinical guideline. Strengths of the study are the natural setting, the training of full staff, the random allocation to the conditions, the large scale of the study and the willingness of both staff and management to participate in the study.
Trial registration
Dutch trial register: NTR3092
PMCID: PMC3551842  PMID: 23302322
Guideline; Implementation; Suicide prevention; Train-the-trainer; E-learning; Healthcare professionals
17.  Type II diabetes patients in primary care: profiles of healthcare utilization obtained from observational data 
The high burden of diabetes for healthcare costs and their impact on quality of life and management of the disease have triggered the design and introduction of disease management programmes (DMPs) in many countries. The extent to which diabetes patients vary with regard to their healthcare utilisation and costs is largely unknown and could impact on the design of DMPs. The objectives of this study are to develop profiles based on both the diabetes-related healthcare utilisation and total healthcare utilisation in primary care, to investigate which patient and disease characteristics determine ‘membership’ of each profile, and to investigate the association between these profiles.
Data were used from electronic medical records of 6721 known type II diabetes patients listed in 48 Dutch general practices. Latent Class Analyses were conducted to identify profiles of healthcare and regression analyses were used to analyse the characteristics of the profiles.
For both diabetes-related healthcare utilisation and total healthcare utilisation three profiles could be distinguished: for the diabetes-related healthcare utilisation these were characterised as ‘high utilisation and frequent home visits’ (n=393), ‘low utilisation, GP only’ (n=3231) and ‘high utilisation, GP and nurse’ (n=3097). Profiles differed with respect to the patients’ age and type of medication; the oldest patients using insulin were dominant in the ‘high utilisation, GP and nurse’ profile. High total healthcare utilisation was not associated with high diabetes-related healthcare utilisation.
Healthcare utilisation of diabetes patients is heterogeneous. This challenges the development of distinguishable DMPs.
PMCID: PMC3570342  PMID: 23289605
Type II diabetes mellitus; Healthcare utilisation profiles; Primary care; Latent Class Analyses
18.  Childhood Atopic Diseases and Early Life Circumstances: An Ecological Study in Cuba 
PLoS ONE  2012;7(6):e39892.
Children are especially vulnerable during periods of resource shortage such as economic embargoes. They are likely to suffer most from poor nutrition, infectious diseases, and other ensuing short-term threats. Moreover, early life circumstances can have important consequences for long-term health. We examined the relationship between early childhood exposure to the Cuban economic situation in the nineties and the occurrence of atopic diseases later in childhood.
Methodology/Principal Findings
A cross-sectional study of 1321 primary schoolchildren aged 4–14 was conducted in two Cuban municipalities. Asthma, allergic rhinoconjunctivitis and atopic dermatitis were diagnosed using the International Study of Asthma and Allergies in Childhood questionnaire. Children were divided into three groups of exposure to the economic situation in the nineties according to birth date: (1) unexposed; (2) exposed during infancy; (3) exposed during infancy and early childhood. Associations were assessed using multiple logistic regression models. Exposure during infancy had a significant inverse association with the occurrence of asthma (OR 0.56, 95%CI 0.33–0.94) and allergic rhinoconjunctivitis (OR 0.46, 95%CI 0.25–0.85). The associations were stronger after longer exposure, i.e. during infancy and early childhood, for asthma (OR 0.40, 95% CI 0.17–0.95) and allergic rhinoconjunctivitis (OR 0.29, 95%CI 0.11–0.77). No significant associations were found for atopic dermatitis.
Exposure to the economic situation in the nineties during infancy and early childhood was inversely associated with asthma and allergic rhinoconjunctivitis occurrence later in childhood. We hypothesize that factors related to this period, such as infectious diseases and undernutrition, may have an attenuating effect on atopic disease development. The exact cause and underlying mechanisms need to be further elucidated.
PMCID: PMC3387214  PMID: 22768156
19.  Cumulative Low Back Load at Work as a Risk Factor of Low Back Pain: A Prospective Cohort Study 
Purpose Much research has been performed on physical exposures during work (e.g. lifting, trunk flexion or body vibrations) as risk factors for low back pain (LBP), however results are inconsistent. Information on the effect of doses (e.g. spinal force or low back moments) on LBP may be more reliable but is lacking yet. The aim of the present study was to investigate the prospective relationship of cumulative low back loads (CLBL) with LBP and to compare the association of this mechanical load measure to exposure measures used previously. Methods The current study was part of the Study on Musculoskeletal disorders, Absenteeism and Health (SMASH) study in which 1,745 workers completed questionnaires. Physical load at the workplace was assessed by video-observations and force measurements. These measures were used to calculate CLBL. Furthermore, a 3-year follow-up was conducted to assess the occurrence of LBP. Logistic regressions were performed to assess associations of CLBL and physical risk factors established earlier (i.e. lifting and working in a flexed posture) with LBP. Furthermore, CLBL and the risk factors combined were assessed as predictors in logistic regression analyses to assess the association with LBP. Results Results showed that CLBL is a significant risk factor for LBP (OR: 2.06 (1.32–3.20)). Furthermore, CLBL had a more consistent association with LBP than two of the three risk factors reported earlier. Conclusions From these results it can be concluded that CLBL is a risk factor for the occurrence of LBP, having a more consistent association with LBP compared to most risk factors reported earlier.
PMCID: PMC3563950  PMID: 22718286
Low back loading; Ergonomics; Workers; Longitudinal studies; Observational studies
20.  The relationship between body composition and physical fitness in 14 year old adolescents residing within the Tlokwe local municipality, South Africa: The PAHL study 
BMC Public Health  2012;12:374.
Little is known about the relationship between body composition and physical fitness in 14 year-old high school adolescents of South Africa. Baseline data from a longitudinal study on physical activity and health (PAHLS) may provide valuable information for future studies, hence to inform public health policy makers. The objectives of this study are to determine the prevalence of underweight, normal weight and overweight among adolescents aged 14 years in the Tlokwe Local Municipality of the North West Province of South Africa, and to assess the association between physical fitness and body composition separately for boys and girls, adjusted for race and locality.
Body weight, height and triceps, and subscapular skinfolds of 256 adolescents (100 boys and 156 girls) aged 14 years were measured, and percentage body fat and body mass index (BMI) were calculated. BMI was used to determine underweight, normal weight and overweight based on the standard criterion. Physical fitness was assessed by standing broad jump, bent arm hang and sit-ups according to the EUROFIT fitness standard procedures. Multinomial logistic regression analyses stratified for gender and adjusted for race (black or white), and the locality (urban or township) of the schools were used to analyze the data.
In the total group 35.9% were underweight and 13.7% overweight. Boys were more underweight (44%) than girls (30.7%). The prevalence of overweight was 8% in boys and 17.3% in girls. BMI was strongly (p = 0.01) related with percentage body fat. Strong and significant positive associations between physical fitness and BMI for the underweight girls with high physical fitness scores (OR, 10.69 [95%CI: 2.81-40.73], and overweight girls with high physical fitness scores (OR, 0.11 [95%CI: 0.03-0.50]) were found. Non-significant weaker positive relationship between physical fitness and BMI for the underweight boys with high physical fitness scores (OR, 1.80 [95%CI: 0.63-5.09]), and the overweight boys with high physical fitness scores (OR, 0.18 [95%CI: 0.02-1.78]) were found.
Both underweight and overweight among boys and girls in Tlokwe Local Municipality exist, and their effects on physical fitness performances were also noticed. As such, strategic physical activity, interventions or follow-up studies recognizing this relationship particularly in the overweight adolescents are needed. In addition, authorities in health and education departments dealing with adolescents should make use of this evidence base information in policies development.
PMCID: PMC3461487  PMID: 22626033
Physical fitness; Body composition; Underweight; Overweight; Adolescents; PAHL study
21.  Implementing the chronic care model for frail older adults in the Netherlands: study protocol of ACT (frail older adults: care in transition) 
BMC Geriatrics  2012;12:19.
Care for older adults is facing a number of challenges: health problems are not consistently identified at a timely stage, older adults report a lack of autonomy in their care process, and care systems are often confronted with the need for better coordination between health care professionals. We aim to address these challenges by introducing the geriatric care model, based on the chronic care model, and to evaluate its effects on the quality of life of community-dwelling frail older adults.
In a 2-year stepped-wedge cluster randomised clinical trial with 6-monthly measurements, the chronic care model will be compared with usual care. The trial will be carried out among 35 primary care practices in two regions in the Netherlands. Per region, practices will be randomly allocated to four allocation arms designating the starting point of the intervention. Participants: 1200 community-dwelling older adults aged 65 or over and their primary informal caregivers. Primary care physicians will identify frail individuals based on a composite definition of frailty and a polypharmacy criterion. Final inclusion criterion: scoring 3 or more on a disability case-finding tool. Intervention: Every 6 months patients will receive a geriatric in-home assessment by a practice nurse, followed by a tailored care plan. Expert teams will manage and train practice nurses. Patients with complex care needs will be reviewed in interdisciplinary consultations. Evaluation: We will perform an effect evaluation, an economic evaluation, and a process evaluation. Primary outcome is quality of life as measured with the Short Form-12 questionnaire. Effect analyses will be based on the “intention-to-treat” principle, using multilevel regression analysis. Cost measurements will be administered continually during the study period. A cost-effectiveness analysis and cost-utility analysis will be conducted comparing mean total costs to functional status, care needs and QALYs. We will investigate the level of implementation, barriers and facilitators to successful implementation and the extent to which the intervention manages to achieve the transition necessary to overcome challenges in elderly care.
This is one of the first studies assessing the effectiveness, cost-effectiveness and implementation process of the chronic care model for frail community-dwelling older adults.
Trial registration
The Netherlands National Trial Register NTR2160.
PMCID: PMC3464922  PMID: 22545816
Chronic care model; Frailty; Elderly; Primary care; Stepped wedge cluster randomised controlled clinical trial
22.  Is a Severe Clinical Profile an Effect Modifier in a Web-Based Depression Treatment for Adults With Type 1 or Type 2 Diabetes? Secondary Analyses From a Randomized Controlled Trial 
Depression and diabetes are two highly prevalent and co-occurring health problems. Web-based, diabetes-specific cognitive behavioral therapy (CBT) depression treatment is effective in diabetes patients, and has the potential to be cost effective and to have large reach. A remaining question is whether the effectiveness differs between patients with seriously impaired mental health and patients with less severe mental health problems.
To test whether the effectiveness of an eight-lesson Web-based, diabetes-specific CBT for depression, with minimal therapist support, differs in patients with or without diagnosed major depressive disorder (MDD), diagnosed anxiety disorder, or elevated diabetes-specific emotional distress (DM-distress).
We used data of 255 patients with diabetes with elevated depression scores, who were recruited via an open access website for participation in a randomized controlled trial, conducted in 2008–2009, comparing a diabetes-specific, Web-based, therapist-supported CBT with a 12-week waiting-list control group. We performed secondary analyses on these data to study whether MDD or anxiety disorder (measured using a telephone-administered diagnostic interview) and elevated DM-distress (online self-reported) are effect modifiers in the treatment of depressive symptoms (online self-reported) with Web-based diabetes-specific CBT.
MDD, anxiety disorder, and elevated DM-distress were not significant effect modifiers in the treatment of self-assessed depressive symptoms with Web-based diabetes-specific CBT.
This Web-based diabetes-specific CBT depression treatment is suitable for use in patients with severe mental health problems and those with a less severe clinical profile.
International Standard Randomized Controlled Trial Number (ISRCTN): 24874457; (Archived by WebCite at
PMCID: PMC3846344  PMID: 22262728
Diabetes mellitus, type 1; diabetes mellitus, type 2; depression; behavior therapy; cognitive therapy; depressive disorder; adults; psychology
23.  Improved clinical outcome after invasive management of patients with recent myocardial infarction and proven myocardial viability: primary results of a randomized controlled trial (VIAMI-trial) 
Trials  2012;13:1.
Patients with ST-elevation myocardial infarction (STEMI) not treated with primary or rescue percutaneous coronary intervention (PCI) are at risk for recurrent ischemia, especially when viability in the infarct-area is present. Therefore, an invasive strategy with PCI of the infarct-related coronary artery in patients with viability would reduce the occurrence of a composite end point of death, reinfarction, or unstable angina (UA).
Patients admitted with an (sub)acute myocardial infarction, who were not treated by primary or rescue PCI, and who were stable during the first 48 hours after the acute event, were screened for the study. Eventually, we randomly assigned 216 patients with viability (demonstrated with low-dose dobutamine echocardiography) to an invasive or a conservative strategy. In the invasive strategy stenting of the infarct-related coronary artery was intended with abciximab as adjunct treatment. Seventy-five (75) patients without viability served as registry group. The primary endpoint was the composite of death from any cause, recurrent myocardial infarction (MI) and unstable angina at one year. As secondary endpoint the need for (repeat) revascularization procedures and anginal status were recorded.
The primary combined endpoint of death, recurrent MI and unstable angina was 7.5% (8/106) in the invasive group and 17.3% (19/110) in the conservative group (Hazard ratio 0.42; 95% confidence interval [CI] 0.18-0.96; p = 0.032). During follow up revascularization-procedures were performed in 6.6% (7/106) in the invasive group and 31.8% (35/110) in the conservative group (Hazard ratio 0.18; 95% CI 0.13-0.43; p < 0.0001). A low rate of recurrent ischemia was found in the non-viable group (5.4%) in comparison to the viable-conservative group (14.5%). (Hazard-ratio 0.35; 95% CI 0.17-1.00; p = 0.051).
We demonstrated that after acute MI (treated with thrombolysis or without reperfusion therapy) patients with viability in the infarct-area benefit from a strategy of early in-hospital stenting of the infarct-related coronary artery. This treatment results in a long-term uneventful clinical course. The study confirmed the low risk of recurrent ischemia in patients without viability.
Trial registration NCT00149591.
PMCID: PMC3261086  PMID: 22214287
24.  Liver Fat Content in Type 2 Diabetes: Relationship With Hepatic Perfusion and Substrate Metabolism 
Diabetes  2010;59(11):2747-2754.
Hepatic steatosis is common in type 2 diabetes. It is causally linked to the features of the metabolic syndrome, liver cirrhosis, and cardiovascular disease. Experimental data have indicated that increased liver fat may impair hepatic perfusion and metabolism. The aim of the current study was to assess hepatic parenchymal perfusion, together with glucose and fatty acid metabolism, in relation to hepatic triglyceride content.
Fifty-nine men with well controlled type 2 diabetes and 18 age-matched healthy normoglycemic men were studied using positron emission tomography to assess hepatic tissue perfusion, insulin-stimulated glucose, and fasting fatty acid metabolism, respectively, in relation to hepatic triglyceride content, quantified by proton magnetic resonance spectroscopy. Patients were divided into two groups with hepatic triglyceride content below (type 2 diabetes-low) or above (type 2 diabetes-high) the median of 8.6%.
Type 2 diabetes-high patients had the highest BMI and A1C and lowest whole-body insulin sensitivity (ANOVA, all P < 0.001). Compared with control subjects and type 2 diabetes-low patients, type 2 diabetes-high patients had the lowest hepatic parenchymal perfusion (P = 0.004) and insulin-stimulated hepatic glucose uptake (P = 0.013). The observed decrease in hepatic fatty acid influx rate constant, however, only reached borderline significance (P = 0.088). In type 2 diabetic patients, hepatic parenchymal perfusion (r = −0.360, P = 0.007) and hepatic fatty acid influx rate constant (r = −0.407, P = 0.007) correlated inversely with hepatic triglyceride content. In a pooled analysis, hepatic fat correlated with hepatic glucose uptake (r = −0.329, P = 0.004).
In conclusion, type 2 diabetic patients with increased hepatic triglyceride content showed decreased hepatic parenchymal perfusion and hepatic insulin mediated glucose uptake, suggesting a potential modulating effect of hepatic fat on hepatic physiology.
PMCID: PMC2963532  PMID: 20693345
25.  For whom and under what circumstances do school-based energy balance behavior interventions work? Systematic review on moderators 
The aim of this review was to systematically review the results and quality of studies investigating the moderators of school-based interventions aimed at energy balance-related behaviors. We systematically searched the electronic databases of Pubmed, EMBASE, Cochrane, PsycInfo, ERIC and Sportdiscus. In total 61 articles were included. Gender, ethnicity, age, baseline values of outcomes, initial weight status and socioeconomic status were the most frequently studied potential moderators. The moderator with the most convincing evidence was gender. School-based interventions appear to work better for girls than for boys. Due to the inconsistent results, many studies reporting non-significant moderating effects, and the moderate methodological quality of most studies, no further consistent results were found. Consequently, there is lack of insight into what interventions work for whom. Future studies should apply stronger methodology to test moderating effects of important potential target group segmentations.
PMCID: PMC3190836  PMID: 21651421
Children; diet; intervention; moderator; overweight; physical activity

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