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1.  [No title available] 
Heart  2007;93(10):1293.
PMCID: PMC2000926
elderly; clopidogrel; glycoprotein IIb/IIIa blockers
2.  Effects of platelet glycoprotein IIb/IIIa receptor blockers in non‐ST segment elevation acute coronary syndromes: benefit and harm in different age subgroups 
Heart  2006;93(4):450-455.
Objective
To investigate whether the beneficial and harmful effects of platelet glycoprotein IIb/IIIa receptor blockers in non‐ST elevation acute coronary syndromes (NSTE‐ACS) depend on age.
Methods
A meta‐analysis of six trials of platelet glycoprotein IIb/IIIa receptor blockers in patients with NSTE‐ACS (PRISM, PRISM‐PLUS, PARAGON‐A, PURSUIT, PARAGON‐B, GUSTO IV‐ACS; n = 31 402) was performed. We applied multivariable logistic regression analyses to evaluate the drug effects on death or non‐fatal myocardial infarction at 30 days, and on major bleeding, by age subgroups (<60, 60–69, 70–79, ⩾80 years). We quantified the reduction of death or myocardial infarction as the number needed to treat (NNT), and the increase of major bleeding as the number needed to harm (NNH).
Results
Subgroups had 11 155 (35%), 9727 (31%), 8468 (27%) and 2049 (7%) patients, respectively. The relative benefit of platelet glycoprotein IIb/IIIa receptor blockers did not differ significantly (p = 0.5) between age subgroups (OR (95% CI) for death or myocardial infarction: 0.86 (0.74 to 0.99), 0.90 (0.80 to 1.02), 0.97 (0.86 to 1.10), 0.90 (0.73 to 1.16); overall 0.91 (0.86 to 0.99). ORs for major bleeding were 1.9 (1.3 to 2.8), 1.9 (1.4 to 2.7), 1.6 (1.2 to 2.1) and 2.5 (1.5–4.1). Overall NNT was 105, and overall NNH was 90. The oldest patients had larger absolute increases in major bleeding, but also had the largest absolute reductions of death or myocardial infarction. Patients ⩾80 years had half of the NNT and a third of the NNH of patients <60 years.
Conclusions
In patients with NSTE‐ACS, the relative reduction of death or non‐fatal myocardial infarction with platelet glycoprotein IIb/IIIa receptor blockers was independent of patient age. Larger absolute outcome reductions were seen in older patients, but with a higher risk of major bleeding. Close monitoring of these patients is warranted.
doi:10.1136/hrt.2006.098657
PMCID: PMC1861476  PMID: 17065179
3.  Glasgow Coma Scale Motor Score and Pupillary Reaction To Predict Six-Month Mortality in Patients with Traumatic Brain Injury: Comparison of Field and Admission Assessment 
Journal of Neurotrauma  2015;32(2):101-108.
Abstract
The Glasgow Coma Scale (GCS) and pupillary reactivity are well-known prognostic factors in traumatic brain injury (TBI). The aim of this study was to compare the GCS motor score and pupillary reactivity assessed in the field and at hospital admission and assess their prognostic value for 6-month mortality in patients with moderate or severe TBI. We studied 445 patients with moderate or severe TBI from Austria enrolled to hospital in 2009–2012. The area under the curve (AUC) and Nagelkerke's R2 were used to evaluate the predictive ability of GCS motor score and pupillary reactivity assessed in the field and at admission. Uni- and multi-variable analyses—adjusting for age, other clinical, and computed tomography findings—were performed using combinations of field and admission GCS motor score and pupillary reactivity. Motor scores generally deteriorated from the field to admission, whereas pupillary reactivity was similar. GCS motor score assessed in field (AUC=0.754; R2=0.273) and pupillary assessment at admission (AUC=0.662; R2=0.214) performed best as predictors of 6-month mortality in the univariate analysis. This combination also showed best performance in the adjusted analyses (AUC=0.876; R2=0.508), but the performance of both predictors assessed at admission was not much worse (AUC=0.857; R2=0.460). Field GCS motor score and pupillary reactivity at hospital admission, compared to other combinations of these parameters, possess the best prognostic value to predict 6-month mortality in patients with moderate-to-severe TBI. Given that differences in prognostic performance are only small, both the field and admission values of GCS motor score and pupillary reaction may be reasonable to use in multi-variable prediction models to predict 6-month outcome.
doi:10.1089/neu.2014.3438
PMCID: PMC4291088  PMID: 25227136
assessment at admission; Glasgow Coma Scale; prehospital assessment; pupillary reactivity; traumatic brain injuries
4.  Advancing the care for traumatic brain injury: summary results from the IMPACT studies and perspectives on future research 
Lancet neurology  2013;12(12):1200-1210.
Research in Traumatic Brain Injury (TBI) is challenging because of many differences between patients. Advances in basic science have failed to translate into successful clinical treatments and the evidence underpinning guideline recommendations is low. Clinical research has been hampered by lack of standardized data collection, limited multidisciplinary collaboration and by insensitive approaches to classification and efficacy analyses. Multidisciplinary collaborations are now being fostered. Approaches for dealing with heterogeneity have been developed by the IMPACT study group. These can increase statistical power in clinical trials by up to 50% and are also relevant to other heterogeneous neurological diseases, such as stroke and subarachnoid hemorrhage. Rather than trying to limit heterogeneity, we may also be able to exploit it by analyzing differences in treatment and outcome between countries and centers in comparative effectiveness designs. This concept offers an additional research approach with great potential to advance the care in TBI.
doi:10.1016/S1474-4422(13)70234-5
PMCID: PMC3895622  PMID: 24139680
5.  Performance of IMPACT, CRASH and Nijmegen models in predicting six month outcome of patients with severe or moderate TBI: an external validation study 
Background
External validation on different TBI populations is important in order to assess the generalizability of prognostic models to different settings. We aimed to externally validate recently developed models for prediction of six month unfavourable outcome and six month mortality.
Methods
The International Neurotrauma Research Organization – Prehospital dataset (INRO-PH) was collected within an observational study between 2009-2012 in Austria and includes 778 patients with TBI of GCS < = 12. Three sets of prognostic models were externally validated: the IMPACT core and extended models, CRASH basic models and the Nijmegen models developed by Jacobs et al – all for prediction of six month unfavourable outcome and six month mortality. The external validity of the models was assessed by discrimination (Area Under the receiver operating characteristic Curve, AUC) and calibration (calibration statistics and plots).
Results
Median age in the validation cohort was 50 years and 44% had an admission GSC motor score of 1-3. Six-month mortality was 27%. Mortality could better be predicted (AUCs around 0.85) than unfavourable outcome (AUCs around 0.80). Calibration plots showed that the observed outcomes were systematically better than was predicted for all models considered. The best performance was noted for the original Nijmegen model, but refitting led to similar performance for the IMPACT Extended, CRASH Basic, and Nijmegen models.
Conclusions
In conclusion, all the prognostic models we validated in this study possess good discriminative ability for prediction of six month outcome in patients with moderate or severe TBI but outcomes were systemically better than predicted. After adjustment for this under prediction in locally adapted models, these may well be used for recent TBI patients.
doi:10.1186/s13049-014-0068-9
PMCID: PMC4267426  PMID: 25406964
Prognostic model; External validation; Traumatic brain injury; Outcome prediction
6.  Is the Readmission Rate a Valid Quality Indicator? A Review of the Evidence 
PLoS ONE  2014;9(11):e112282.
Introduction
Hospital readmission rates are increasingly used for both quality improvement and cost control. However, the validity of readmission rates as a measure of quality of hospital care is not evident. We aimed to give an overview of the different methodological aspects in the definition and measurement of readmission rates that need to be considered when interpreting readmission rates as a reflection of quality of care.
Methods
We conducted a systematic literature review, using the bibliographic databases Embase, Medline OvidSP, Web-of-Science, Cochrane central and PubMed for the period of January 2001 to May 2013.
Results
The search resulted in 102 included papers. We found that definition of the context in which readmissions are used as a quality indicator is crucial. This context includes the patient group and the specific aspects of care of which the quality is aimed to be assessed. Methodological flaws like unreliable data and insufficient case-mix correction may confound the comparison of readmission rates between hospitals. Another problem occurs when the basic distinction between planned and unplanned readmissions cannot be made. Finally, the multi-faceted nature of quality of care and the correlation between readmissions and other outcomes limit the indicator's validity.
Conclusions
Although readmission rates are a promising quality indicator, several methodological concerns identified in this study need to be addressed, especially when the indicator is intended for accountability or pay for performance. We recommend investing resources in accurate data registration, improved indicator description, and bundling outcome measures to provide a more complete picture of hospital care.
doi:10.1371/journal.pone.0112282
PMCID: PMC4224424  PMID: 25379675
7.  Predictive Value of Four Kallikrein Markers for Pathologically Insignificant Compared With Aggressive Prostate Cancer in Radical Prostatectomy Specimens: Results From the European Randomized Study of Screening for Prostate Cancer Section Rotterdam 
European urology  2013;64(5):693-699.
Background
Treatment decisions can be difficult in men with low-risk prostate cancer (PCa).
Objective
To evaluate the ability of a panel of four kallikrein markers in blood—total prostate-specific antigen (PSA), free PSA, intact PSA, and kallikrein-related peptidase 2—to distinguish between pathologically insignificant and aggressive disease on pathologic examination of radical prostatectomy (RP) specimens as well as to calculate the number of avoidable surgeries.
Design, setting, and participants
The cohort comprised 392 screened men participating in rounds 1 and 2 of the Rotterdam arm of the European Randomized Study of Screening for Prostate Cancer. Patients were diagnosed with PCa because of an elevated PSA ≥3.0 ng/ml and were treated with RP between 1994 and 2004.
Outcome measurements and statistical analysis
We calculated the accuracy (area under the curve [AUC]) of statistical models to predict pathologically aggressive PCa (pT3–T4, extracapsular extension, tumor volume >0.5 cm3, or any Gleason grade ≥4) based on clinical predictors (age, stage, PSA, biopsy findings) with and without levels of four kallikrein markers in blood.
Results and limitations
A total of 261 patients (67%) had significant disease on pathologic evaluation of the RP specimen. While the clinical model had good accuracy in predicting aggressive disease, reflected in a corrected AUC of 0.81, the four kallikrein markers enhanced the base model, with an AUC of 0.84 (p < 0.0005). The model retained its ability in patients with low-risk and very-low-risk disease and in comparison with the Steyerberg nomogram, a published prediction model. Clinical application of the model incorporating the kallikrein markers would reduce rates of surgery by 135 of 1000 patients overall and 110 of 334 patients with pathologically insignificant disease. A limitation of the present study is that clinicians may be hesitant to make recommendations against active treatment on the basis of a statistical model.
Conclusions
Our study provided proof of principle that predictions based on levels of four kallikrein markers in blood distinguish between pathologically insignificant and aggressive disease after RP with good accuracy. In the future, clinical use of the model could potentially reduce rates of immediate unnecessary active treatment.
doi:10.1016/j.eururo.2013.04.040
PMCID: PMC3786059  PMID: 23683475
Prostate-specific antigen/blood; Prostatic neoplasms; Mass screening; Radical prostatectomy; Kallikrein-related peptidases
8.  Long-term outcome of ruptured abdominal aortic aneurysm: impact of treatment and age 
Background
Despite advances in operative repair, ruptured abdominal aortic aneurysm (rAAA) remains associated with high mortality and morbidity rates, especially in elderly patients. The purpose of this study was to evaluate the outcomes of emergency endovascular aneurysm repair (eEVAR), conventional open repair (OPEN), and conservative treatment in elderly patients with rAAA.
Methods
We conducted a retrospective study of all rAAA patients treated with OPEN or eEVAR between January 2005 and December 2011 in the vascular surgery department at Amphia Hospital, the Netherlands. The outcome in patients treated for rAAA by eEVAR or OPEN repair was investigated. Special attention was paid to patients who were admitted and did not receive operative intervention due to serious comorbidity, extremely advanced age, or poor physical condition. We calculated the 30-day rAAA-related mortality for all rAAA patients admitted to our hospital.
Results
Twelve patients did not receive operative emergency repair due to extreme fragility (mean age 87 years, median time to mortality 27 hours). Twenty-three patients had eEVAR and 82 had OPEN surgery. The 30-day mortality rate in operated patients was 30% (7/23) in the eEVAR group versus 26% (21/82) in the OPEN group (P=0.64). No difference in mortality was noted between eEVAR and OPEN over 5 years of follow-up. There were more cardiac adverse events in the OPEN group (n=25, 31%) than in the eEVAR group (n=2, 9%; P=0.035). Reintervention after discharge was more frequent in patients who received eEVAR (35%) than in patients who had OPEN (6%, P<0.001). Advancing age was associated with increasing mortality (hazard ratio 1.05 [95% confidence interval 1.01–1.09]) per year for patients who received operative repair, with a 67%, 76%, and 100% 5-year mortality rate in the 34 patients aged <70 years, 59 patients aged 70–79 years, and 12 octogenarians, respectively; 30-day rAAA-related mortality was also associated with increasing age (21%, 30%, and 61%, respectively; P=0.008).
Conclusion
The 30-day and 5-year mortality in patients who survived rAAA was equal between the treatment options of eEVAR and OPEN. Particularly fragile and very elderly patients did not receive operative repair. The decision to intervene in rAAA should not be made on the basis of patient age alone, but also in relation to comorbidity and patient preference.
doi:10.2147/CIA.S64718
PMCID: PMC4206251  PMID: 25342890
ruptured abdominal aneurysm repair; clinical decision-making; emergency endovascular aneurysm repair; open repair
9.  Racial and Ethnic Variations in the Effects of Family History of Colorectal Cancer on Screening Compliance 
Gastroenterology  2013;145(4):775-781.e2.
Background & Aims
Individuals with a family history of colorectal cancer (CRC) have a higher risk of developing CRC than the general population, and studies have shown that they are more likely to undergo CRC screening. We assessed the overall and race- and ethnic-specific effects of a family history of CRC on screening.
Methods
We analyzed data from the 2009 California Health Interview Survey to estimate overall and race- and ethnicity-specific odds ratios (ORs) for the association between family history of CRC and CRC screening.
Results
The unweighted and weighted sample sizes were 23,837 and 8,851,003, respectively. Individuals with a family history of CRC were more likely to participate in any form of screening (OR, 2.3; 95% confidence limit [CL], 1.7–3.1) and in colonoscopy screening (OR, 2.7; 95% CL, 2.2–3.4) than those without a family history, but this association varied among racial and ethnic groups. The magnitude of the association between family history and colonoscopy screening was highest among Asians (OR, 6.1; 95% CL, 3.1–11.9), lowest among Hispanics (OR, 1.4; 95% CL, 0.67–2.8), and comparable between non-Hispanic Whites (OR, 3.1; 95% CL, 2.6–3.8) and non-Hispanic Blacks (OR 2.6; 95% CL, 1.2–5.7) (P for interaction <0.001).
Conclusions
The effects of family history of CRC on participation in screening vary among racial and ethnic groups, and have the lowest effects on Hispanics, compared with other groups. Consequently, interventions to promote CRC screening among Hispanics with a family history should be considered.
doi:10.1053/j.gastro.2013.06.037
PMCID: PMC3783551  PMID: 23796457
population study; database analysis; early detection; colon cancer prevention
10.  Acceptance of Vaccinations in Pandemic Outbreaks: A Discrete Choice Experiment 
PLoS ONE  2014;9(7):e102505.
Background
Preventive measures are essential to limit the spread of new viruses; their uptake is key to their success. However, the vaccination uptake in pandemic outbreaks is often low. We aim to elicit how disease and vaccination characteristics determine preferences of the general public for new pandemic vaccinations.
Methods
In an internet-based discrete choice experiment (DCE) a representative sample of 536 participants (49% participation rate) from the Dutch population was asked for their preference for vaccination programs in hypothetical communicable disease outbreaks. We used scenarios based on two disease characteristics (susceptibility to and severity of the disease) and five vaccination program characteristics (effectiveness, safety, advice regarding vaccination, media attention, and out-of-pocket costs). The DCE design was based on a literature review, expert interviews and focus group discussions. A panel latent class logit model was used to estimate which trade-offs individuals were willing to make.
Results
All above mentioned characteristics proved to influence respondents’ preferences for vaccination. Preference heterogeneity was substantial. Females who stated that they were never in favor of vaccination made different trade-offs than males who stated that they were (possibly) willing to get vaccinated. As expected, respondents preferred and were willing to pay more for more effective vaccines, especially if the outbreak was more serious (€6–€39 for a 10% more effective vaccine). Changes in effectiveness, out-of-pocket costs and in the body that advises the vaccine all substantially influenced the predicted uptake.
Conclusions
We conclude that various disease and vaccination program characteristics influence respondents’ preferences for pandemic vaccination programs. Agencies responsible for preventive measures during pandemics can use the knowledge that out-of-pocket costs and the way advice is given affect vaccination uptake to improve their plans for future pandemic outbreaks. The preference heterogeneity shows that information regarding vaccination needs to be targeted differently depending on gender and willingness to get vaccinated.
doi:10.1371/journal.pone.0102505
PMCID: PMC4109921  PMID: 25057914
11.  Improving the Transparency of Prognosis Research: The Role of Reporting, Data Sharing, Registration, and Protocols 
PLoS Medicine  2014;11(7):e1001671.
George Peat and colleagues review and discuss current approaches to transparency and published debates and concerns about efforts to standardize prognosis research practice, and make five recommendations.
Please see later in the article for the Editors' Summary
doi:10.1371/journal.pmed.1001671
PMCID: PMC4086727  PMID: 25003600
12.  Measuring Quality Improvement in Acute Ischemic Stroke Care: Interrupted Time Series Analysis of Door-to-Needle Time 
Cerebrovascular Diseases Extra  2014;4(2):149-155.
Background
In patients with acute ischemic stroke, early treatment with recombinant tissue plasminogen activator (rtPA) improves functional outcome by effectively reducing disability and dependency. Timely thrombolysis, within 1 h, is a vital aspect of acute stroke treatment, and is reflected in the widely used performance indicator ‘door-to-needle time’ (DNT). DNT measures the time from the moment the patient enters the emergency department until he/she receives intravenous rtPA. The purpose of the study was to measure quality improvement from the first implementation of thrombolysis in stroke patients in a university hospital in the Netherlands. We further aimed to identify specific interventions that affect DNT.
Methods
We included all patients with acute ischemic stroke consecutively admitted to a large university hospital in the Netherlands between January 2006 and December 2012, and focused on those treated with thrombolytic therapy on admission. Data were collected routinely for research purposes and internal quality measurement (the Erasmus Stroke Study). We used a retrospective interrupted time series design to study the trend in DNT, analyzed by means of segmented regression.
Results
Between January 2006 and December 2012, 1,703 patients with ischemic stroke were admitted and 262 (17%) were treated with rtPA. Patients treated with thrombolysis were on average 63 years old at the time of the stroke and 52% were male. Mean age (p = 0.58) and sex distribution (p = 0.98) did not change over the years. The proportion treated with thrombolysis increased from 5% in 2006 to 22% in 2012. In 2006, none of the patients were treated within 1 h. In 2012, this had increased to 81%. In a logistic regression analysis, this trend was significant (OR 1.6 per year, CI 1.4-1.8). The median DNT was reduced from 75 min in 2006 to 45 min in 2012 (p < 0.001 in a linear regression model). In this period, a 12% annual decrease in DNT was achieved (CI from 16 to 8%). We could not find a significant association between any specific intervention and the trend in DNT.
Conclusion and Implications
The DNT steadily improved from the first implementation of thrombolysis. Specific explanations for this improvement require further study, and may relate to the combined impact of a series of structural and logistic interventions. Our results support the use of performance measures for internal communication. Median DNT should be used on a monthly or quarterly basis to inform all professionals treating stroke patient of their achievements.
doi:10.1159/000363535
PMCID: PMC4105950  PMID: 25076959
Acute ischemic stroke; Acute stroke care; Door-to-needle time; Recombinant tissue plasminogen activator; Performance indicator; Quality of care; Process indicators; Quality improvement
13.  Evaluation of markers and risk prediction models: Overview of relationships between NRI and decision-analytic measures 
BACKGROUND
For the evaluation and comparison of markers and risk prediction models, various novel measures have recently been introduced as alternatives to the commonly used difference in the area under the ROC curve (ΔAUC). The Net Reclassification Improvement (NRI) is increasingly popular to compare predictions with one or more risk thresholds, but decision-analytic approaches have also been proposed.
OBJECTIVE
We aimed to identify the mathematical relationships between novel performance measures for the situation that a single risk threshold T is used to classify patients as having the outcome or not.
METHODS
We considered the NRI and three utility-based measures that take misclassification costs into account: difference in Net Benefit (ΔNB), difference in Relative Utility (ΔRU), and weighted NRI (wNRI). We illustrate the behavior of these measures in 1938 women suspect of ovarian cancer (prevalence 28%).
RESULTS
The three utility-based measures appear transformations of each other, and hence always lead to consistent conclusions. On the other hand, conclusions may differ when using the standard NRI, depending on the adopted risk threshold T, prevalence P and the obtained differences in sensitivity and specificity of the two models that are compared. In the case study, adding the CA-125 tumor marker to a baseline set of covariates yielded a negative NRI yet a positive value for the utility-based measures.
CONCLUSIONS
The decision-analytic measures are each appropriate to indicate the clinical usefulness of an added marker or compare prediction models, since these measures each reflect misclassification costs. This is of practical importance as these measures may thus adjust conclusions based on purely statistical measures. A range of risk thresholds should be considered in applying these measures.
doi:10.1177/0272989X12470757
PMCID: PMC4066820  PMID: 23313931
14.  Prediction of Survival with Alternative Modeling Techniques Using Pseudo Values 
PLoS ONE  2014;9(6):e100234.
Background
The use of alternative modeling techniques for predicting patient survival is complicated by the fact that some alternative techniques cannot readily deal with censoring, which is essential for analyzing survival data. In the current study, we aimed to demonstrate that pseudo values enable statistically appropriate analyses of survival outcomes when used in seven alternative modeling techniques.
Methods
In this case study, we analyzed survival of 1282 Dutch patients with newly diagnosed Head and Neck Squamous Cell Carcinoma (HNSCC) with conventional Kaplan-Meier and Cox regression analysis. We subsequently calculated pseudo values to reflect the individual survival patterns. We used these pseudo values to compare recursive partitioning (RPART), neural nets (NNET), logistic regression (LR) general linear models (GLM) and three variants of support vector machines (SVM) with respect to dichotomous 60-month survival, and continuous pseudo values at 60 months or estimated survival time. We used the area under the ROC curve (AUC) and the root of the mean squared error (RMSE) to compare the performance of these models using bootstrap validation.
Results
Of a total of 1282 patients, 986 patients died during a median follow-up of 66 months (60-month survival: 52% [95% CI: 50%−55%]). The LR model had the highest optimism corrected AUC (0.791) to predict 60-month survival, followed by the SVM model with a linear kernel (AUC 0.787). The GLM model had the smallest optimism corrected RMSE when continuous pseudo values were considered for 60-month survival or the estimated survival time followed by SVM models with a linear kernel. The estimated importance of predictors varied substantially by the specific aspect of survival studied and modeling technique used.
Conclusions
The use of pseudo values makes it readily possible to apply alternative modeling techniques to survival problems, to compare their performance and to search further for promising alternative modeling techniques to analyze survival time.
doi:10.1371/journal.pone.0100234
PMCID: PMC4065009  PMID: 24950066
15.  Risk Prediction Scores for Recurrence and Progression of Non-Muscle Invasive Bladder Cancer: An International Validation in Primary Tumours 
PLoS ONE  2014;9(6):e96849.
Objective
We aimed to determine the validity of two risk scores for patients with non-muscle invasive bladder cancer in different European settings, in patients with primary tumours.
Methods
We included 1,892 patients with primary stage Ta or T1 non-muscle invasive bladder cancer who underwent a transurethral resection in Spain (n = 973), the Netherlands (n = 639), or Denmark (n = 280). We evaluated recurrence-free survival and progression-free survival according to the European Organisation for Research and Treatment of Cancer (EORTC) and the Spanish Urological Club for Oncological Treatment (CUETO) risk scores for each patient and used the concordance index (c-index) to indicate discriminative ability.
Results
The 3 cohorts were comparable according to age and sex, but patients from Denmark had a larger proportion of patients with the high stage and grade at diagnosis (p<0.01). At least one recurrence occurred in 839 (44%) patients and 258 (14%) patients had a progression during a median follow-up of 74 months. Patients from Denmark had the highest 10-year recurrence and progression rates (75% and 24%, respectively), whereas patients from Spain had the lowest rates (34% and 10%, respectively). The EORTC and CUETO risk scores both predicted progression better than recurrence with c-indices ranging from 0.72 to 0.82 while for recurrence, those ranged from 0.55 to 0.61.
Conclusion
The EORTC and CUETO risk scores can reasonably predict progression, while prediction of recurrence is more difficult. New prognostic markers are needed to better predict recurrence of tumours in primary non-muscle invasive bladder cancer patients.
doi:10.1371/journal.pone.0096849
PMCID: PMC4048166  PMID: 24905984
16.  Predictive Value of Updating Framingham Risk Scores with Novel Risk Markers in the U.S. General Population 
PLoS ONE  2014;9(2):e88312.
Background
According to population-based cohort studies CT coronary calcium score (CTCS), carotid intima-media thickness (cIMT), high-sensitivity C- reactive protein (CRP), and ankle-brachial index (ABI) are promising novel risk markers for improving cardiovascular risk assessment. Their impact in the U.S. general population is however uncertain. Our aim was to estimate the predictive value of four novel cardiovascular risk markers for the U.S. general population.
Methods and Findings
Risk profiles, CRP and ABI data of 3,736 asymptomatic subjects aged 40 or older from the National Health and Nutrition Examination Survey (NHANES) 2003–2004 exam were used along with predicted CTCS and cIMT values. For each subject, we calculated 10-year cardiovascular risks with and without each risk marker. Event rates adjusted for competing risks were obtained by microsimulation. We assessed the impact of updated 10-year risk scores by reclassification and C-statistics. In the study population (mean age 56±11 years, 48% male), 70% (80%) were at low (<10%), 19% (14%) at intermediate (≥10–<20%), and 11% (6%) at high (≥20%) 10-year CVD (CHD) risk. Net reclassification improvement was highest after updating 10-year CVD risk with CTCS: 0.10 (95%CI 0.02–0.19). The C-statistic for 10-year CVD risk increased from 0.82 by 0.02 (95%CI 0.01–0.03) with CTCS. Reclassification occurred most often in those at intermediate risk: with CTCS, 36% (38%) moved to low and 22% (30%) to high CVD (CHD) risk. Improvements with other novel risk markers were limited.
Conclusions
Only CTCS appeared to have significant incremental predictive value in the U.S. general population, especially in those at intermediate risk. In future research, cost-effectiveness analyses should be considered for evaluating novel cardiovascular risk assessment strategies.
doi:10.1371/journal.pone.0088312
PMCID: PMC3928195  PMID: 24558385
17.  Improving the Manchester Triage System for Pediatric Emergency Care: An International Multicenter Study 
PLoS ONE  2014;9(1):e83267.
Objectives
This multicenter study examines the performance of the Manchester Triage System (MTS) after changing discriminators, and with the addition use of abnormal vital sign in patients presenting to pediatric emergency departments (EDs).
Design
International multicenter study
Settings
EDs of two hospitals in The Netherlands (2006–2009), one in Portugal (November–December 2010), and one in UK (June–November 2010).
Patients
Children (<16years) triaged with the MTS who presented at the ED.
Methods
Changes to discriminators (MTS 1) and the value of including abnormal vital signs (MTS 2) were studied to test if this would decrease the number of incorrect assignment. Admission to hospital using the new MTS was compared with those in the original MTS. Likelihood ratios, diagnostic odds ratios (DORs), and c-statistics were calculated as measures for performance and compared with the original MTS. To calculate likelihood ratios and DORs, the MTS had to be dichotomized in low urgent and high urgent.
Results
60,375 patients were included, of whom 13% were admitted. When MTS 1 was used, admission to hospital increased from 25% to 29% for MTS ‘very urgent’ patients and remained similar in lower MTS urgency levels. The diagnostic odds ratio improved from 4.8 (95%CI 4.5–5.1) to 6.2 (95%CI 5.9–6.6) and the c-statistic remained 0.74. MTS 2 did not improve the performance of the MTS.
Conclusions
MTS 1 performed slightly better than the original MTS. The use of vital signs (MTS 2) did not improve the MTS performance.
doi:10.1371/journal.pone.0083267
PMCID: PMC3893080  PMID: 24454699
18.  Assessing discriminative ability of risk models in clustered data 
Background
The discriminative ability of a risk model is often measured by Harrell’s concordance-index (c-index). The c-index estimates for two randomly chosen subjects the probability that the model predicts a higher risk for the subject with poorer outcome (concordance probability). When data are clustered, as in multicenter data, two types of concordance are distinguished: concordance in subjects from the same cluster (within-cluster concordance probability) and concordance in subjects from different clusters (between-cluster concordance probability). We argue that the within-cluster concordance probability is most relevant when a risk model supports decisions within clusters (e.g. who should be treated in a particular center). We aimed to explore different approaches to estimate the within-cluster concordance probability in clustered data.
Methods
We used data of the CRASH trial (2,081 patients clustered in 35 centers) to develop a risk model for mortality after traumatic brain injury. To assess the discriminative ability of the risk model within centers we first calculated cluster-specific c-indexes. We then pooled the cluster-specific c-indexes into a summary estimate with different meta-analytical techniques. We considered fixed effect meta-analysis with different weights (equal; inverse variance; number of subjects, events or pairs) and random effects meta-analysis. We reflected on pooling the estimates on the log-odds scale rather than the probability scale.
Results
The cluster-specific c-index varied substantially across centers (IQR = 0.70-0.81; I 2 = 0.76 with 95% confidence interval 0.66 to 0.82). Summary estimates resulting from fixed effect meta-analysis ranged from 0.75 (equal weights) to 0.84 (inverse variance weights). With random effects meta-analysis – accounting for the observed heterogeneity in c-indexes across clusters – we estimated a mean of 0.77, a between-cluster variance of 0.0072 and a 95% prediction interval of 0.60 to 0.95. The normality assumptions for derivation of a prediction interval were better met on the probability than on the log-odds scale.
Conclusion
When assessing the discriminative ability of risk models used to support decisions at cluster level we recommend meta-analysis of cluster-specific c-indexes. Particularly, random effects meta-analysis should be considered.
doi:10.1186/1471-2288-14-5
PMCID: PMC3897966  PMID: 24423445
Clustered data; Concordance; Discrimination; Meta-analysis; Prediction; Risk model
19.  Situational awareness, relational coordination and integrated care delivery to hospitalized elderly in The Netherlands: a comparison between hospitals 
BMC Geriatrics  2014;14:3.
Background
It is known that interprofessional collaboration is crucial for integrated care delivery, yet we are still unclear about the underlying mechanisms explaining effectiveness of integrated care delivery to older patients. In addition, we lack research comparing integrated care delivery between hospitals. Therefore, this study aims to (i) provide insight into the underlying components ‘relational coordination’ and ‘situational awareness’ of integrated care delivery and the role of team and organizational context in integrated care delivery; and (ii) compare situational awareness, relational coordination, and integrated care delivery of different hospitals in the Netherlands.
Methods
This cross-sectional study took place in 2012 among professionals from three different hospitals involved in the delivery of care to older patients. A total of 215 professionals filled in the questionnaire (42% response rate).Descriptive statistics and paired-sample t-tests were used to investigate the level of situational awareness, relational coordination, and integrated care delivery in the three different hospitals. Correlation and multilevel analyses were used to investigate the relationship between background characteristics, team context, organizational context, situational awareness, relational coordination and integrated care delivery.
Results
No differences in background characteristics, team context, organizational context, situational awareness, relational coordination and integrated care delivery were found among the three hospitals. Correlational analysis revealed that situational awareness (r = 0.30; p < 0.01), relational coordination (r = 0.17; p < 0.05), team climate (r = 0.29; p < 0.01), formal internal communication (r = 0.46; p < 0.01), and informal internal communication (r = 0.36; p < 0.01) were positively associated with integrated care delivery. Stepwise multilevel analyses showed that formal internal communication (p < 0.001) and situational awareness (p < 0.01) were associated with integrated care delivery. Team climate was not significantly associated with integrated care delivery when situational awareness and relational coordination were included in the equation. Thus situational awareness acted as mediator between team climate and integrated care delivery among professionals delivering care to older hospitalized patients.
Conclusions
The results of this study show the importance of formal internal communication and situational awareness for quality of care delivery to hospitalized older patients.
doi:10.1186/1471-2318-14-3
PMCID: PMC3890569  PMID: 24410889
20.  The Development of the Older Persons and Informal Caregivers Survey Minimum DataSet (TOPICS-MDS): A Large-Scale Data Sharing Initiative 
PLoS ONE  2013;8(12):e81673.
Introduction
In 2008, the Ministry of Health, Welfare and Sport commissioned the National Care for the Elderly Programme. While numerous research projects in older persons’ health care were to be conducted under this national agenda, the Programme further advocated the development of The Older Persons and Informal Caregivers Survey Minimum DataSet (TOPICS-MDS) which would be integrated into all funded research protocols. In this context, we describe TOPICS data sharing initiative (www.topics-mds.eu).
Materials and Methods
A working group drafted TOPICS-MDS prototype, which was subsequently approved by a multidisciplinary panel. Using instruments validated for older populations, information was collected on demographics, morbidity, quality of life, functional limitations, mental health, social functioning and health service utilisation. For informal caregivers, information was collected on demographics, hours of informal care and quality of life (including subjective care-related burden).
Results
Between 2010 and 2013, a total of 41 research projects contributed data to TOPICS-MDS, resulting in preliminary data available for 32,310 older persons and 3,940 informal caregivers. The majority of studies sampled were from primary care settings and inclusion criteria differed across studies.
Discussion
TOPICS-MDS is a public data repository which contains essential data to better understand health challenges experienced by older persons and informal caregivers. Such findings are relevant for countries where increasing health-related expenditure has necessitated the evaluation of contemporary health care delivery. Although open sharing of data can be difficult to achieve in practice, proactively addressing issues of data protection, conflicting data analysis requests and funding limitations during TOPICS-MDS developmental phase has fostered a data sharing culture. To date, TOPICS-MDS has been successfully incorporated into 41 research projects, thus supporting the feasibility of constructing a large (>30,000 observations), standardised dataset pooled from various study protocols with different sampling frameworks. This unique implementation strategy improves efficiency and facilitates individual-level data meta-analysis.
doi:10.1371/journal.pone.0081673
PMCID: PMC3852259  PMID: 24324716
21.  Prevalence and Phenotypes of APC and MUTYH Mutations in Patients with Multiple Colorectal Adenomas 
Context
Patients with multiple colorectal adenomas may carry germline mutations in the APC or MUTYH genes.
Objectives
To determine the prevalence of pathogenic APC and MUTYH mutations in patients who had undergone genetic testing and compare the prevalence and clinical characteristics of APC and MUTYH mutation carriers.
Design, Setting and Participants
This cross-sectional study consisted of 8676 unrelated individuals who had undergone full gene sequencing and large rearrangement analysis of the APC gene and targeted sequence analysis for the two most common MUTYH mutations (Y179C and G396D) between 2004 and 2011. Individuals with either mutation underwent full MUTYH gene sequencing. We evaluated APC and MUTYH mutation prevalence by polyp burden and the clinical characteristics associated with a pathogenic mutation using logistic regression analyses.
Main Outcome Measure
Deleterious mutations in APC and MUTYH genes.
Results
Colorectal adenomas were reported in 7225 individuals; 1457 with classic polyposis (≥ 100 adenomas) and 3253 with attenuated polyposis (20-99 adenomas). The prevalence of APC and biallelic MUTYH mutations was 95/119 (80%, 95%CI 71-87%) and 2/119 (2%, 95%CI 0.2-6%) among individuals with ≥ 1000 adenomas, 756/1338 (56%, 95%CI 54-59%) and 94/1338 (7%, 95%CI 6-8%) among individuals with 100-999 adenomas, 326/3253 (10%, 95%CI (9-11%) and 233/3253 (7%, 95%CI 6-8%) among individuals with 20-99 adenomas, and 50/970 (5%, 95%CI 4-7%) and 37/970 (4%, 95%CI 3-5%) among those with 10-19 adenomas.
Conclusions
Among patients with multiple colorectal adenomas, APC and MUTYH mutation prevalence varied considerably by adenoma count including within those with a classic polyposis phenotype. APC mutations predominate in patients with classic polyposis, whereas prevalence of APC and MYH mutations is similar in attenuated polyposis. These findings require external validation.
doi:10.1001/jama.2012.8780
PMCID: PMC3770297  PMID: 22851115
22.  Individual participant data meta-analyses should not ignore clustering 
Journal of Clinical Epidemiology  2013;66(8):865-873.e4.
Objectives
Individual participant data (IPD) meta-analyses often analyze their IPD as if coming from a single study. We compare this approach with analyses that rather account for clustering of patients within studies.
Study Design and Setting
Comparison of effect estimates from logistic regression models in real and simulated examples.
Results
The estimated prognostic effect of age in patients with traumatic brain injury is similar, regardless of whether clustering is accounted for. However, a family history of thrombophilia is found to be a diagnostic marker of deep vein thrombosis [odds ratio, 1.30; 95% confidence interval (CI): 1.00, 1.70; P = 0.05] when clustering is accounted for but not when it is ignored (odds ratio, 1.06; 95% CI: 0.83, 1.37; P = 0.64). Similarly, the treatment effect of nicotine gum on smoking cessation is severely attenuated when clustering is ignored (odds ratio, 1.40; 95% CI: 1.02, 1.92) rather than accounted for (odds ratio, 1.80; 95% CI: 1.29, 2.52). Simulations show models accounting for clustering perform consistently well, but downwardly biased effect estimates and low coverage can occur when ignoring clustering.
Conclusion
Researchers must routinely account for clustering in IPD meta-analyses; otherwise, misleading effect estimates and conclusions may arise.
doi:10.1016/j.jclinepi.2012.12.017
PMCID: PMC3717206  PMID: 23651765
Individual participant data meta-analysis; Individual patient data; Evidence synthesis; Cluster; Simulation; Binary outcome; Pooled analysis
23.  Comparison of Scoring Methods for ACE-27: Simpler Is Better 
Journal of geriatric oncology  2012;3(3):238-245.
Objective
To examine the prognostic value of different comorbidity coding schemes for predicting survival of newly diagnosed elderly cancer patients.
Materials and Methods
We analyzed data from 8,867 patients aged 65 years of age or older, newly diagnosed with cancer. Comorbidities present at the time of diagnosis were collected using the Adult Comorbidity Evaluation-27 index (ACE-27). We examined multiple scoring schemes based on the individual comorbidity ailments, and their severity rating. Harrell’s c index and Akaike Information Criterion (AIC) were used to evaluate the performance of the different comorbidity models.
Results
Comorbidity led to an increase in c index from 0.771 for the base model to 0.782 for a model that included indicator variables for every ailment. The prognostic value was however much higher for prostate and breast cancer patients. A simple model which considered linear scores from 0 to 3 per ailment, controlling for cancer type, was optimal according to AIC.
Conclusion
The presence of comorbidity impacts on the survival of elderly cancer patients, especially for less lethal cancers, such as prostate and breast cancers. Different ailments have different impacts on survival, necessitating the use of different weights per ailment in a simple summary score of the ACE-27.
doi:10.1016/j.jgo.2012.01.006
PMCID: PMC3375822  PMID: 22712031
Comorbidity; comorbid ailment; elderly; cancer patients; prognostic; survival
24.  Influences of hospital information systems, indicator data collection and computation on reported Dutch hospital performance indicator scores 
Background
For health care performance indicators (PIs) to be reliable, data underlying the PIs are required to be complete, accurate, consistent and reproducible. Given the lack of regulation of the data-systems used in the Netherlands, and the self-report based indicator scores, one would expect heterogeneity with respect to the data collection and the ways indicators are computed. This might affect the reliability and plausibility of the nationally reported scores.
Methods
We aimed to investigate the extent to which local hospital data collection and indicator computation strategies differ and how this affects the plausibility of self-reported indicator scores, using survey results of 42 hospitals and data of the Dutch national quality database.
Results
The data collection and indicator computation strategies of the hospitals were substantially heterogenic. Moreover, the Hip and Knee replacement PI scores can be regarded as largely implausible, which was, to a great extent, related to a limited (computerized) data registry. In contrast, Breast Cancer PI scores were more plausible, despite the incomplete data registry and limited data access. This might be explained by the role of the regional cancer centers that collect most of the indicator data for the national cancer registry, in a standardized manner. Hospitals can use cancer registry indicator scores to report to the government, instead of their own locally collected indicator scores.
Conclusions
Indicator developers, users and the scientific field need to focus more on the underlying (heterogenic) ways of data collection and conditional data infrastructures. Countries that have a liberal software market and are aiming to implement a self-report based performance indicator system to obtain health care transparency, should secure the accuracy and precision of the heath care data from which the PIs are calculated. Moreover, ongoing research and development of PIs and profound insight in the clinical practice of data registration is warranted.
doi:10.1186/1472-6963-13-212
PMCID: PMC3698115  PMID: 23758921
Performance indicators; Health care quality; Reliability; Hospital information system
25.  Predicting 14-Day Mortality after Severe Traumatic Brain Injury: Application of the IMPACT Models in the Brain Trauma Foundation TBI-trac® New York State Database 
Journal of Neurotrauma  2012;29(7):1306-1312.
Abstract
Prognostic models for outcome prediction in patients with traumatic brain injury (TBI) are important instruments in both clinical practice and research. To remain current a continuous process of model validation is necessary. We aimed to investigate the performance of the International Mission on Prognosis and Analysis of Clinical Trials in TBI (IMPACT) prognostic models in predicting mortality in a contemporary New York State TBI registry developed and maintained by the Brain Trauma Foundation. The Brain Trauma Foundation (BTF) TBI-trac® database contains data on 3125 patients who sustained severe TBI (Glasgow Coma Scale [GCS] score ≤8) in New York State between 2000 and 2009. The outcome measure was 14-day mortality. To predict 14-day mortality with admission data, we adapted the IMPACT Core and Extended models. Performance of the models was assessed by determining calibration (agreement between observed and predicted outcomes), and discrimination (separation of those patients who die from those who survive). Calibration was explored graphically with calibration plots. Discrimination was expressed by the area under the receiver operating characteristic (ROC) curve (AUC). A total of 2513 out of 3125 patients in the BTF database met the inclusion criteria. The 14-day mortality rate was 23%. The models showed excellent calibration. Mean predicted probabilities were 20% for the Core model and 24% for the Extended model. Both models showed good discrimination with AUCs of 0.79 (Core) and 0.83 (Extended). We conclude that the IMPACT models validly predict 14-day mortality in the BTF database, confirming generalizability of these models for outcome prediction in TBI patients.
doi:10.1089/neu.2011.1988
PMCID: PMC3335134  PMID: 22150207
external validation; outcome; prediction models; traumatic brain injury

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