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1.  Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): the TRIPOD Statement 
BMC Medicine  2015;13:1.
Prediction models are developed to aid health care providers in estimating the probability or risk that a specific disease or condition is present (diagnostic models) or that a specific event will occur in the future (prognostic models), to inform their decision making. However, the overwhelming evidence shows that the quality of reporting of prediction model studies is poor. Only with full and clear reporting of information on all aspects of a prediction model can risk of bias and potential usefulness of prediction models be adequately assessed. The Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) Initiative developed a set of recommendations for the reporting of studies developing, validating, or updating a prediction model, whether for diagnostic or prognostic purposes. This article describes how the TRIPOD Statement was developed. An extensive list of items based on a review of the literature was created, which was reduced after a Web-based survey and revised during a 3-day meeting in June 2011 with methodologists, health care professionals, and journal editors. The list was refined during several meetings of the steering group and in e-mail discussions with the wider group of TRIPOD contributors. The resulting TRIPOD Statement is a checklist of 22 items, deemed essential for transparent reporting of a prediction model study. The TRIPOD Statement aims to improve the transparency of the reporting of a prediction model study regardless of the study methods used. The TRIPOD Statement is best used in conjunction with the TRIPOD explanation and elaboration document. To aid the editorial process and readers of prediction model studies, it is recommended that authors include a completed checklist in their submission (also available at
Editors’ note: In order to encourage dissemination of the TRIPOD Statement, this article is freely accessible on the Annals of Internal Medicine Web site ( and will be also published in BJOG, British Journal of Cancer, British Journal of Surgery, BMC Medicine, British Medical Journal, Circulation, Diabetic Medicine, European Journal of Clinical Investigation, European Urology, and Journal of Clinical Epidemiology. The authors jointly hold the copyright of this article. An accompanying Explanation and Elaboration article is freely available only on; Annals of Internal Medicine holds copyright for that article.
PMCID: PMC4284921  PMID: 25563062
Prediction models; Prognostic; Diagnostic; Model development; Validation; Transparency; Reporting
2.  Internet-Based Early Intervention to Prevent Posttraumatic Stress Disorder in Injury Patients: Randomized Controlled Trial 
Posttraumatic stress disorder (PTSD) develops in 10-20% of injury patients. We developed a novel, self-guided Internet-based intervention (called Trauma TIPS) based on techniques from cognitive behavioral therapy (CBT) to prevent the onset of PTSD symptoms.
To determine whether Trauma TIPS is effective in preventing the onset of PTSD symptoms in injury patients.
Adult, level 1 trauma center patients were randomly assigned to receive the fully automated Trauma TIPS Internet intervention (n=151) or to receive no early intervention (n=149). Trauma TIPS consisted of psychoeducation, in vivo exposure, and stress management techniques. Both groups were free to use care as usual (nonprotocolized talks with hospital staff). PTSD symptom severity was assessed at 1, 3, 6, and 12 months post injury with a clinical interview (Clinician-Administered PTSD Scale) by blinded trained interviewers and self-report instrument (Impact of Event Scale—Revised). Secondary outcomes were acute anxiety and arousal (assessed online), self-reported depressive and anxiety symptoms (Hospital Anxiety and Depression Scale), and mental health care utilization. Intervention usage was documented.
The mean number of intervention logins was 1.7, SD 2.5, median 1, interquartile range (IQR) 1-2. Thirty-four patients in the intervention group did not log in (22.5%), 63 (41.7%) logged in once, and 54 (35.8%) logged in multiple times (mean 3.6, SD 3.5, median 3, IQR 2-4). On clinician-assessed and self-reported PTSD symptoms, both the intervention and control group showed a significant decrease over time (P<.001) without significant differences in trend. PTSD at 12 months was diagnosed in 4.7% of controls and 4.4% of intervention group patients. There were no group differences on anxiety or depressive symptoms over time. Post hoc analyses using latent growth mixture modeling showed a significant decrease in PTSD symptoms in a subgroup of patients with severe initial symptoms (n=20) (P<.001).
Our results do not support the efficacy of the Trauma TIPS Internet-based early intervention in the prevention of PTSD symptoms for an unselected population of injury patients. Moreover, uptake was relatively low since one-fifth of individuals did not log in to the intervention. Future research should therefore focus on innovative strategies to increase intervention usage, for example, adding gameplay, embedding it in a blended care context, and targeting high-risk individuals who are more likely to benefit from the intervention.
Trial Registration
International Standard Randomized Controlled Trial Number (ISRCTN): 57754429; (Archived by WebCite at
PMCID: PMC3742408  PMID: 23942480
early intervention; prevention; Internet; posttraumatic stress disorder; cognitive behavior therapy
3.  Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies: The CHARMS Checklist 
PLoS Medicine  2014;11(10):e1001744.
Carl Moons and colleagues provide a checklist and background explanation for critically appraising and extracting data from systematic reviews of prognostic and diagnostic prediction modelling studies.
Please see later in the article for the Editors' Summary
PMCID: PMC4196729  PMID: 25314315
4.  Latent class bivariate model for the meta-analysis of diagnostic test accuracy studies 
Several types of statistical methods are currently available for the meta-analysis of studies on diagnostic test accuracy. One of these methods is the Bivariate Model which involves a simultaneous analysis of the sensitivity and specificity from a set of studies. In this paper, we review the characteristics of the Bivariate Model and demonstrate how it can be extended with a discrete latent variable. The resulting clustering of studies yields additional insight into the accuracy of the test of interest.
A Latent Class Bivariate Model is proposed. This model captures the between-study variability in sensitivity and specificity by assuming that studies belong to one of a small number of latent classes. This yields both an easier to interpret and a more precise description of the heterogeneity between studies. Latent classes may not only differ with respect to the average sensitivity and specificity, but also with respect to the correlation between sensitivity and specificity.
The Latent Class Bivariate Model identifies clusters of studies with their own estimates of sensitivity and specificity. Our simulation study demonstrated excellent parameter recovery and good performance of the model selection statistics typically used in latent class analysis. Application in a real data example on coronary artery disease showed that the inclusion of latent classes yields interesting additional information.
Our proposed new meta-analysis method can lead to a better fit of the data set of interest, less biased estimates and more reliable confidence intervals for sensitivities and specificities. But even more important, it may serve as an exploratory tool for subsequent sub-group meta-analyses.
PMCID: PMC4105799  PMID: 25015209
Meta-analysis; Meta-regression; Bivariate model; Latent class model
5.  Comparing Screening Instruments to Predict Posttraumatic Stress Disorder 
PLoS ONE  2014;9(5):e97183.
Following traumatic exposure, a proportion of trauma victims develops posttraumatic stress disorder (PTSD). Early PTSD risk screening requires sensitive instruments to identify everyone at risk for developing PTSD in need of diagnostic follow-up.
This study compares the accuracy of the 4-item SPAN, 10-item Trauma Screening Questionnaire (TSQ) and 22-item Impact of Event Scale-Revised (IES-R) in predicting chronic PTSD at a minimum sensitivity of 80%.
Injury patients admitted to a level-I trauma centre (N = 311) completed the instruments at a median of 23 days and were clinically assessed for PTSD at 6 months. Areas under the curve and specificities at 80% sensitivity were compared between instruments.
Areas under the curve in all instruments were adequate (SPAN: 0.83; TSQ: 0.82; IES-R: 0.83) with no significant differences. At 80% sensitivity, specificities were 64% for SPAN, 59% for TSQ and 72% for IES-R.
The SPAN, TSQ and IES-R show similar accuracy in early detection of individuals at risk for PTSD, despite differences in number of items. The modest specificities and low positive predictive values found for all instruments could lead to relatively many false positive cases, when applied in clinical practice.
PMCID: PMC4016271  PMID: 24816642
6.  Incorporating quality assessments of primary studies in the conclusions of diagnostic accuracy reviews: a cross-sectional study 
Drawing conclusions from systematic reviews of test accuracy studies without considering the methodological quality (risk of bias) of included studies may lead to unwarranted optimism about the value of the test(s) under study. We sought to identify to what extent the results of quality assessment of included studies are incorporated in the conclusions of diagnostic accuracy reviews.
We searched MEDLINE and EMBASE for test accuracy reviews published between May and September 2012. We examined the abstracts and main texts of these reviews to see whether and how the results of quality assessment were linked to the accuracy estimates when drawing conclusions.
We included 65 reviews of which 53 contained a meta-analysis. Sixty articles (92%) had formally assessed the methodological quality of included studies, most often using the original QUADAS tool (n = 44, 68%). Quality assessment was mentioned in 28 abstracts (43%); with a majority (n = 21) mentioning it in the methods section. In only 5 abstracts (8%) were results of quality assessment incorporated in the conclusions. Thirteen reviews (20%) presented results of quality assessment in the main text only, without further discussion. Forty-seven reviews (72%) discussed results of quality assessment; the most frequent form was as limitations in assessing quality (n = 28). Only 6 reviews (9%) further linked the results of quality assessment to their conclusions, 3 of which did not conduct a meta-analysis due to limitations in the quality of included studies. In the reviews with a meta-analysis, 19 (36%) incorporated quality in the analysis. Eight reported significant effects of quality on the pooled estimates; in none of them these effects were factored in the conclusions.
While almost all recent diagnostic accuracy reviews evaluate the quality of included studies, very few consider results of quality assessment when drawing conclusions. The practice of reporting systematic reviews of test accuracy should improve if readers not only want to be informed about the limitations in the available evidence, but also on the associated implications for the performance of the evaluated tests.
PMCID: PMC3942773  PMID: 24588874
Diagnostic tests; Test accuracy; Systematic reviews; Meta-analysis; Quality; QUADAS; Risk of bias
7.  Use of Expert Panels to Define the Reference Standard in Diagnostic Research: A Systematic Review of Published Methods and Reporting 
PLoS Medicine  2013;10(10):e1001531.
Loes C. M. Bertens and colleagues survey the published diagnostic research literature for use of expert panels to define the reference standard, characterize components and missing information, and recommend elements that should be reported in diagnostic studies.
Please see later in the article for the Editors' Summary
In diagnostic studies, a single and error-free test that can be used as the reference (gold) standard often does not exist. One solution is the use of panel diagnosis, i.e., a group of experts who assess the results from multiple tests to reach a final diagnosis in each patient. Although panel diagnosis, also known as consensus or expert diagnosis, is frequently used as the reference standard, guidance on preferred methodology is lacking. The aim of this study is to provide an overview of methods used in panel diagnoses and to provide initial guidance on the use and reporting of panel diagnosis as reference standard.
Methods and Findings
PubMed was systematically searched for diagnostic studies applying a panel diagnosis as reference standard published up to May 31, 2012. We included diagnostic studies in which the final diagnosis was made by two or more persons based on results from multiple tests. General study characteristics and details of panel methodology were extracted. Eighty-one studies were included, of which most reported on psychiatry (37%) and cardiovascular (21%) diseases. Data extraction was hampered by incomplete reporting; one or more pieces of critical information about panel reference standard methodology was missing in 83% of studies. In most studies (75%), the panel consisted of three or fewer members. Panel members were blinded to the results of the index test results in 31% of studies. Reproducibility of the decision process was assessed in 17 (21%) studies. Reported details on panel constitution, information for diagnosis and methods of decision making varied considerably between studies.
Methods of panel diagnosis varied substantially across studies and many aspects of the procedure were either unclear or not reported. On the basis of our review, we identified areas for improvement and developed a checklist and flow chart for initial guidance for researchers conducting and reporting of studies involving panel diagnosis.
Please see later in the article for the Editors' Summary
Editors' Summary
Before any disease or condition can be treated, a correct diagnosis of the condition has to be made. Faced with a patient with medical problems and no diagnosis, a doctor will ask the patient about their symptoms and medical history and generally will examine the patient. On the basis of this questioning and examination, the clinician will form an initial impression of the possible conditions the patient may have, usually with a most likely diagnosis in mind. To support or reject the most likely diagnosis and to exclude the other possible diagnoses, the clinician will then order a series of tests and diagnostic procedures. These may include laboratory tests (such as the measurement of blood sugar levels), imaging procedures (such as an MRI scan), or functional tests (such as spirometry, which tests lung function). Finally, the clinician will use all the data s/he has collected to reach a firm diagnosis and will recommend a program of treatment or observation for the patient.
Why Was This Study Done?
Researchers are continually looking for new, improved diagnostic tests and multivariable diagnostic models—combinations of tests and characteristics that point to a diagnosis. Diagnostic research, which assesses the accuracy of new tests and models, requires that each patient involved in a diagnostic study has a final correct diagnosis. Unfortunately, for most conditions, there is no single, error-free test that can be used as the reference (gold) standard for diagnosis. If an imperfect reference standard is used, errors in the final disease classification may bias the results of the diagnostic study and may lead to a new test being adopted that is actually less accurate than existing tests. One widely used solution to the lack of a reference standard is “panel diagnosis” in which two or more experts assess the results from multiple tests to reach a final diagnosis for each patient in a diagnostic study. However, there is currently no formal guidance available on the conduct and reporting of panel diagnosis. Here, the researchers undertake a systematic review (a study that uses predefined criteria to identify research on a given topic) to provide an overview of the methodology and reporting of panel diagnosis.
What Did the Researchers Do and Find?
The researchers identified 81 published diagnostic studies that used panel diagnosis as a reference standard. 37% of these studies reported on psychiatric diseases, 21% reported on cardiovascular diseases, and 12% reported on respiratory diseases. Most of the studies (64%) were designed to assess the accuracy of one or more diagnostic test. Notably, one or more critical piece of information on methodology was missing in 83% of the studies. Specifically, information on the constitution of the panel was missing in a quarter of the studies and information on the decision-making process (whether, for example, a diagnosis was reached by discussion among panel members or by combining individual panel member's assessments) was incomplete in more than two-thirds of the studies. In three-quarters of the studies for which information was available, the panel consisted of only two or three members; different fields of expertise were represented in the panels in nearly two-thirds of the studies. In a third of the studies for which information was available, panel members made their diagnoses without access to the results of the test being assessed. Finally, the reproducibility of the decision-making process was assessed in a fifth of the studies.
What Do These Findings Mean?
These findings indicate that the methodology of panel diagnosis varies substantially among diagnostic studies and that reporting of this methodology is often unclear or absent. Both the methodology and reporting of panel diagnosis could, therefore, be improved substantially. Based on their findings, the researchers provide a checklist and flow chart to help guide the conduct and reporting of studies involving panel diagnosis. For example, they suggest that, when designing a study that uses panel diagnosis as the reference standard, the number and background of panel members should be considered, and they provide a list of options that should be considered when planning the decision-making process. Although more research into each of the options identified by the researchers is needed, their recommendations provide a starting point for the development of formal guidelines on the methodology and reporting of panel diagnosis for use as a reference standard in diagnostic research.
Additional Information
Please access these Web sites via the online version of this summary at
Wikipedia has a page on medical diagnosis (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The Equator Network is an international initiative that seeks to improve the reliability and value of medical research literature by promoting transparent and accurate reporting of research studies; its website includes information on a wide range of reporting guidelines, including the STAndards for the Reporting of Diagnostic accuracy studies (STARD), an initiative that aims to improve the accuracy and completeness of reporting of studies of diagnostic accuracy
PMCID: PMC3797139  PMID: 24143138
8.  Development and validation of a model to predict the risk of exacerbations in chronic obstructive pulmonary disease 
Prediction models for exacerbations in patients with chronic obstructive pulmonary disease (COPD) are scarce. Our aim was to develop and validate a new model to predict exacerbations in patients with COPD.
Patients and methods
The derivation cohort consisted of patients aged 65 years or over, with a COPD diagnosis, who were followed up over 24 months. The external validation cohort consisted of another cohort of COPD patients, aged 50 years or over. Exacerbations of COPD were defined as symptomatic deterioration requiring pulsed oral steroid use or hospitalization. Logistic regression analysis including backward selection and shrinkage were used to develop the final model and to adjust for overfitting. The adjusted regression coefficients were applied in the validation cohort to assess calibration of the predictions and calculate changes in discrimination applying C-statistics.
The derivation and validation cohort consisted of 240 and 793 patients with COPD, of whom 29% and 28%, respectively, experienced an exacerbation during follow-up. The final model included four easily assessable variables: exacerbations in the previous year, pack years of smoking, level of obstruction, and history of vascular disease, with a C-statistic of 0.75 (95% confidence interval [CI]: 0.69–0.82). Predictions were well calibrated in the validation cohort, with a small loss in discrimination potential (C-statistic 0.66 [95% CI 0.61–0.71]).
Our newly developed prediction model can help clinicians to predict the risk of future exacerbations in individual patients with COPD, including those with mild disease.
PMCID: PMC3797610  PMID: 24143086
exacerbation of COPD; risk prediction; external validation; vascular disease
9.  The impact of the HEART risk score in the early assessment of patients with acute chest pain: design of a stepped wedge, cluster randomised trial 
Chest pain remains a diagnostic challenge: physicians do not want to miss an acute coronary syndrome (ACS), but, they also wish to avoid unnecessary additional diagnostic procedures. In approximately 75% of the patients presenting with chest pain at the emergency department (ED) there is no underlying cardiac cause. Therefore, diagnostic strategies focus on identifying patients in whom an ACS can be safely ruled out based on findings from history, physical examination and early cardiac marker measurement. The HEART score, a clinical prediction rule, was developed to provide the clinician with a simple, early and reliable predictor of cardiac risk. We set out to quantify the impact of the use of the HEART score in daily practice on patient outcomes and costs.
We designed a prospective, multi-centre, stepped wedge, cluster randomised trial. Our aim is to include a total of 6600 unselected chest pain patients presenting at the ED in 10 Dutch hospitals during an 11-month period. All clusters (i.e. hospitals) start with a period of ‘usual care’ and are randomised in their timing when to switch to ‘intervention care’. The latter involves the calculation of the HEART score in each patient to guide clinical decision; notably reassurance and discharge of patients with low scores and intensive monitoring and early intervention in patients with high HEART scores. Primary outcome is occurrence of major adverse cardiac events (MACE), including acute myocardial infarction, revascularisation or death within 6 weeks after presentation. Secondary outcomes include occurrence of MACE in low-risk patients, quality of life, use of health care resources and costs.
Stepped wedge designs are increasingly used to evaluate the real-life effectiveness of non-pharmacological interventions because of the following potential advantages: (a) each hospital has both a usual care and an intervention period, therefore, outcomes can be compared within and across hospitals; (b) each hospital will have an intervention period which enhances participation in case of a promising intervention; (c) all hospitals generate data about potential implementation problems. This large impact trial will generate evidence whether the anticipated benefits (in terms of safety and cost-effectiveness) of using the HEART score will indeed be achieved in real-life clinical practice.
Trial registration 80-82310-97-12154.
PMCID: PMC3849098  PMID: 24070098
HEART score; Chest pain; Clinical prediction rule; Risk score implementation; Impact; Stepped wedge design; Cluster randomised trial
10.  Variation of a test’s sensitivity and specificity with disease prevalence 
Anecdotal evidence suggests that the sensitivity and specificity of a diagnostic test may vary with disease prevalence. Our objective was to investigate the associations between disease prevalence and test sensitivity and specificity using studies of diagnostic accuracy.
We used data from 23 meta-analyses, each of which included 10–39 studies (416 total). The median prevalence per review ranged from 1% to 77%. We evaluated the effects of prevalence on sensitivity and specificity using a bivariate random-effects model for each meta-analysis, with prevalence as a covariate. We estimated the overall effect of prevalence by pooling the effects using the inverse variance method.
Within a given review, a change in prevalence from the lowest to highest value resulted in a corresponding change in sensitivity or specificity from 0 to 40 percentage points. This effect was statistically significant (p < 0.05) for either sensitivity or specificity in 8 meta-analyses (35%). Overall, specificity tended to be lower with higher disease prevalence; there was no such systematic effect for sensitivity.
The sensitivity and specificity of a test often vary with disease prevalence; this effect is likely to be the result of mechanisms, such as patient spectrum, that affect prevalence, sensitivity and specificity. Because it may be difficult to identify such mechanisms, clinicians should use prevalence as a guide when selecting studies that most closely match their situation.
PMCID: PMC3735771  PMID: 23798453
11.  A decision rule to aid selection of patients with abdominal sepsis requiring a relaparotomy 
BMC Surgery  2013;13:28.
Accurate and timely identification of patients in need of a relaparotomy is challenging since there are no readily available strongholds. The aim of this study is to develop a prediction model to aid the decision-making process in whom to perform a relaparotomy.
Data from a randomized trial comparing surgical strategies for relaparotomy were used. Variables were selected based on previous reports and common clinical sense and screened in a univariable regression analysis to identify those associated with the need for relaparotomy. Variables with the strongest association were considered for the prediction model which was constructed after backward elimination in a multivariable regression analysis. The discriminatory capacity of the model was expressed with the area under the curve (AUC). A cut-off analysis was performed to illustrate the consequences in clinical practice.
One hundred and eighty-two patients were included; 46 were considered cases requiring a relaparotomy. A prediction model was build containing 6 variables. This final model had an AUC of 0.80 indicating good discriminatory capacity. However, acceptable sensitivity would require a low threshold for relaparotomy leading to an unacceptable rate of negative relaparotomies (63%). Therefore, the prediction model was incorporated in a decision rule were the interval until re-assessment and the use of Computed Tomography are related to the outcome of the model.
To construct a prediction model that will provide a definite answer whether or not to perform a relaparotomy seems a utopia. However, our prediction model can be used to stratify patients on their underlying risk and could guide further monitoring of patients with abdominal sepsis in order to identify patients with suspected ongoing peritonitis in a timely fashion.
PMCID: PMC3750491  PMID: 23870702
Secondary peritonitis; Abdominal sepsis; Relaparotomy; On-demand; Prediction model; Decision rule
12.  Serum Mesothelin for Diagnosing Malignant Pleural Mesothelioma: An Individual Patient Data Meta-Analysis 
Journal of Clinical Oncology  2012;30(13):1541-1549.
Mesothelin is currently considered the best available serum biomarker of malignant pleural mesothelioma. To examine the diagnostic accuracy and use of serum mesothelin in early diagnosis, we performed an individual patient data (IPD) meta-analysis.
The literature search identified 16 diagnostic studies of serum mesothelin, measured with the Mesomark enzyme-linked immunosorbent assay. IPD of 4,491 individuals were collected, including several control groups and 1,026 patients with malignant pleural mesothelioma. Mesothelin levels were standardized for between-study differences and age, after which the diagnostic accuracy and the factors affecting it were examined with receiver operating characteristic (ROC) regression analysis.
At a common diagnostic threshold of 2.00 nmol/L, the sensitivities and specificities of mesothelin in the different studies ranged widely from 19% to 68% and 88% to 100%, respectively. This heterogeneity can be explained by differences in study population, because type of control group, mesothelioma stage, and histologic subtype significantly affected the diagnostic accuracy. The use of mesothelin in early diagnosis was evaluated by differentiating 217 patients with stage I or II epithelioid and biphasic mesothelioma from 1,612 symptomatic or high-risk controls. The resulting area under the ROC curve was 0.77 (95% CI, 0.73 to 0.81). At 95% specificity, mesothelin displayed a sensitivity of 32% (95% CI, 26% to 40%).
In patients suspected of having mesothelioma, a positive blood test for mesothelin at a high-specificity threshold is a strong incentive to urge further diagnostic steps. However, the poor sensitivity of mesothelin clearly limits its added value to early diagnosis and emphasizes the need for further biomarker research.
PMCID: PMC3383122  PMID: 22412141
13.  Triage of frail elderly with reduced exercise tolerance in primary care (TREE). a clustered randomized diagnostic study 
BMC Public Health  2012;12:385.
Exercise reduced tolerance and breathlessness are common in the elderly and can result in substantial loss in functionality and health related quality of life. Heart failure (HF) and chronic obstructive pulmonary disease (COPD) are common underlying causes, but can be difficult to disentangle due to overlap in symptomatology. In addition, other potential causes such as obesity, anaemia, renal dysfunction and thyroid disorders may be involved.
We aim to assess whether screening of frail elderly with reduced exercise tolerance leads to high detection rates of HF, COPD, or alternative diagnoses, and whether detection of these diseases would result in changes in patient management and increase in both functionality and quality of life.
A cluster randomized diagnostic trial. Primary care practices are randomized to the diagnostic-treatment strategy (screening) or care as usual.
Patient population: Frail (defined as having three or more chronic or vitality threatening diseases and/or receiving five or more drugs chronically during the last year) community-dwelling persons aged 65 years and older selected from the electronic medical files of the participating general practitioners. Those with reduced exercise tolerance or moderate to severe dyspnoea (≥2 score on the Medical Research Counsel dyspnoea scale) are included in the study.
The diagnostic screening in the intervention group includes history taking, physical examination, electrocardiography, spirometry, blood tests, and echocardiography. Subsequently, participants with new diagnoses will be managed according to clinical guidelines. Participants in the control arm receive care as usual. All participants fill out health status and other relevant questionnaires at baseline and after 6 months of follow-up.
This study will generate information on the yield of screening for previously unrecognized HF, COPD and other chronic diseases in frail elderly with reduced exercise tolerance and/or exercise induced dyspnoea. The cluster randomized comparison will reveal whether this yield will result in subsequent improvements in functional health and/or health related quality of life.
Trial registration NCT01148719
PMCID: PMC3407748  PMID: 22640176
Reduced exercise tolerance; Dyspnoea; Breathlessness; Heart failure; COPD; Frail; Elderly; Screening
14.  A multicenter, randomized controlled trial of immediate total-body CT scanning in trauma patients (REACT-2) 
Computed tomography (CT) scanning has become essential in the early diagnostic phase of trauma care because of its high diagnostic accuracy. The introduction of multi-slice CT scanners and infrastructural improvements made total-body CT scanning technically feasible and its usage is currently becoming common practice in several trauma centers. However, literature provides limited evidence whether immediate total-body CT leads to better clinical outcome then conventional radiographic imaging supplemented with selective CT scanning in trauma patients. The aim of the REACT-2 trial is to determine the value of immediate total-body CT scanning in trauma patients.
The REACT-2 trial is an international, multicenter randomized clinical trial. All participating trauma centers have a multi-slice CT scanner located in the trauma room or at the Emergency Department (ED). All adult, non-pregnant, severely injured trauma patients according to predefined criteria will be included. Patients in whom direct scanning will hamper necessary cardiopulmonary resuscitation or who require an immediate operation because of imminent death (both as judged by the trauma team leader) are excluded. Randomization will be computer assisted. The intervention group will receive a contrast-enhanced total-body CT scan (head to pelvis) during the primary survey. The control group will be evaluated according to local conventional trauma imaging protocols (based on ATLS guidelines) supplemented with selective CT scanning. Primary outcome will be in-hospital mortality. Secondary outcomes are differences in mortality and morbidity during the first year post trauma, several trauma work-up time intervals, radiation exposure, general health and quality of life at 6 and 12 months post trauma and cost-effectiveness.
The REACT-2 trial is a multicenter randomized clinical trial that will provide evidence on the value of immediate total-body CT scanning during the primary survey of severely injured trauma patients. If immediate total-body CT scanning is found to be the best imaging strategy in severely injured trauma patients it could replace conventional imaging supplemented with CT in this specific group.
Trial Registration (NCT01523626).
PMCID: PMC3361475  PMID: 22458247
15.  Validation of a Dutch Risk Score Predicting Poor Outcome in Adults with Bacterial Meningitis in Vietnam and Malawi 
PLoS ONE  2012;7(3):e34311.
We have previously developed and validated a prognostic model to predict the risk for unfavorable outcome in Dutch adults with bacterial meningitis. The aim of the current study was to validate this model in adults with bacterial meningitis from two developing countries, Vietnam and Malawi. Demographic and clinical characteristics of Vietnamese (n = 426), Malawian patients (n = 465) differed substantially from those of Dutch patients (n = 696). The Dutch model underestimated the risk of poor outcome in both Malawi and Vietnam. The discrimination of the original model (c-statistic [c] 0.84; 95% confidence interval 0.81 to 0.86) fell considerably when re-estimated in the Vietnam cohort (c = 0.70) or in the Malawian cohort (c = 0.68). Our validation study shows that new prognostic models have to be developed for these countries in a sufficiently large series of unselected patients.
PMCID: PMC3314623  PMID: 22470555
16.  Failure of available scoring systems to predict ongoing infection in patients with abdominal sepsis after their initial emergency laparotomy 
BMC Surgery  2011;11:38.
To examine commonly used scoring systems, designed to predict overall outcome in critically ill patients, for their ability to select patients with an abdominal sepsis that have ongoing infection needing relaparotomy.
Data from a RCT comparing two surgical strategies was used. The study population consisted of 221 patients at risk for ongoing abdominal infection. The following scoring systems were evaluated with logistic regression analysis for their ability to select patients requiring a relaparotomy: APACHE-II score, SAPS-II, Mannheim Peritonitis Index (MPI), MODS, SOFA score, and the acute part of the APACHE-II score (APS).
The proportion of patients requiring a relaparotomy was 32% (71/221). Only 2 scores had a discriminatory ability in identifying patients with ongoing infection needing relaparotomy above chance: the APS on day 1 (AUC 0.61; 95%CI 0.52-0.69) and the SOFA score on day 2 (AUC 0.60; 95%CI 0.52-0.69). However, to correctly identify 90% of all patients needing a relaparotomy would require such a low cut-off value that around 80% of all patients identified by these scoring systems would have negative findings at relaparotomy.
None of the widely-used scoring systems to predict overall outcome in critically ill patients are of clinical value for the identification of patients with ongoing infection needing relaparotomy. There is a need to develop more specific tools to assist physicians in their daily monitoring and selection of these patients after the initial emergency laparotomy.
Trial registration number
PMCID: PMC3268736  PMID: 22196238
17.  Internet-based prevention of posttraumatic stress symptoms in injured trauma patients: design of a randomized controlled trial 
European Journal of Psychotraumatology  2011;2:10.3402/ejpt.v2i0.8294.
Injured trauma victims are at risk of developing Posttraumatic Stress Disorder (PTSD) and other post-trauma psychopathology. So far, interventions using cognitive behavioral techniques (CBT) have proven most efficacious in treating early PTSD in highly symptomatic individuals. No early intervention for the prevention of PTSD for all victims has yet proven effective. In the acute psychosocial care for trauma victims, there is a clear need for easily applicable, accessible, cost-efficient early interventions.
To describe the design of a randomized controlled trial (RCT) evaluating the effectiveness of a brief Internet-based early intervention that incorporates CBT techniques with the aim of reducing acute psychological distress and preventing long-term PTSD symptoms in injured trauma victims.
In a two armed RCT, 300 injured trauma victims from two Level-1 trauma centers in Amsterdam, the Netherlands, will be assigned to an intervention or a control group. Inclusion criteria are: being 18 years of age or older, having experienced a traumatic event according to the diagnostic criteria of the DSM-IV and understanding the Dutch language. The intervention group will be given access to the intervention's website (, and are specifically requested to login within the first month postinjury. The primary clinical study outcome is PTSD symptom severity. Secondary outcomes include symptoms of depression and anxiety, quality of life, and social support. In addition, a cost-effectiveness analysis of the intervention will be performed. Data are collected at one week post-injury, prior to first login (baseline), and at 1, 3, 6 and 12 months. Analyses will be on an intention-to-treat basis.
The results will provide more insight into the effects of preventive interventions in general, and Internet-based early interventions specifically, on acute stress reactions and PTSD, in an injured population, during the acute phase after trauma. We will discuss possible strengths and limitations.
PMCID: PMC3402131  PMID: 22893814
injury; trauma; early intervention; prevention; Internet; e-Mental Health; PTSD; cognitive behavioral therapy (CBT)
18.  The ladies trial: laparoscopic peritoneal lavage or resection for purulent peritonitisA and Hartmann's procedure or resection with primary anastomosis for purulent or faecal peritonitisB in perforated diverticulitis (NTR2037) 
BMC Surgery  2010;10:29.
Recently, excellent results are reported on laparoscopic lavage in patients with purulent perforated diverticulitis as an alternative for sigmoidectomy and ostomy.
The objective of this study is to determine whether LaparOscopic LAvage and drainage is a safe and effective treatment for patients with purulent peritonitis (LOLA-arm) and to determine the optimal resectional strategy in patients with a purulent or faecal peritonitis (DIVA-arm: perforated DIVerticulitis: sigmoidresection with or without Anastomosis).
In this multicentre randomised trial all patients with perforated diverticulitis are included. Upon laparoscopy, patients with purulent peritonitis are treated with laparoscopic lavage and drainage, Hartmann's procedure or sigmoidectomy with primary anastomosis in a ratio of 2:1:1 (LOLA-arm). Patients with faecal peritonitis will be randomised 1:1 between Hartmann's procedure and resection with primary anastomosis (DIVA-arm). The primary combined endpoint of the LOLA-arm is major morbidity and mortality. A sample size of 132:66:66 patients will be able to detect a difference in the primary endpoint from 25% in resectional groups compared to 10% in the laparoscopic lavage group (two sided alpha = 5%, power = 90%). Endpoint of the DIVA-arm is stoma free survival one year after initial surgery. In this arm 212 patients are needed to significantly demonstrate a difference of 30% (log rank test two sided alpha = 5% and power = 90%) in favour of the patients with resection with primary anastomosis. Secondary endpoints for both arms are the number of days alive and outside the hospital, health related quality of life, health care utilisation and associated costs.
The Ladies trial is a nationwide multicentre randomised trial on perforated diverticulitis that will provide evidence on the merits of laparoscopic lavage and drainage for purulent generalised peritonitis and on the optimal resectional strategy for both purulent and faecal generalised peritonitis.
Trial registration
Nederlands Trial Register NTR2037
PMCID: PMC2974662  PMID: 20955571
19.  A multicenter randomized clinical trial investigating the cost-effectiveness of treatment strategies with or without antibiotics for uncomplicated acute diverticulitis (DIABOLO trial) 
BMC Surgery  2010;10:23.
Conservative treatment of uncomplicated or mild diverticulitis usually includes antibiotic therapy. It is, however, uncertain whether patients with acute diverticulitis indeed benefit from antibiotics. In most guidelines issued by professional organizations antibiotics are considered mandatory in the treatment of mild diverticulitis. This advice lacks evidence and is merely based on experts' opinion. Adverse effects of the use of antibiotics are well known, including allergic reactions, development of bacterial resistance to antibiotics and other side-effects.
A randomized multicenter pragmatic clinical trial comparing two treatment strategies for uncomplicated acute diverticulitis. I) A conservative strategy with antibiotics: hospital admission, supportive measures and at least 48 hours of intravenous antibiotics which subsequently are switched to oral, if tolerated (for a total duration of antibiotic treatment of 10 days). II) A liberal strategy without antibiotics: admission only if needed on clinical grounds, supportive measures only. Patients are eligible for inclusion if they have a diagnosis of acute uncomplicated diverticulitis as demonstrated by radiological imaging. Only patients with stages 1a and 1b according to Hinchey's classification or "mild" diverticulitis according to the Ambrosetti criteria are included. The primary endpoint is time-to-full recovery within a 6-month follow-up period. Full recovery is defined as being discharged from the hospital, with a return to pre-illness activities, and VAS score below 4 without the use of daily pain medication. Secondary endpoints are proportion of patients who develop complicated diverticulitis requiring surgery or non-surgical intervention, morbidity, costs, health-related quality of life, readmission rate and acute diverticulitis recurrence rate. In a non-inferiority design 264 patients are needed in each study arm to detect a difference in time-to-full recovery of 5 days or more with a power of 85% and a confidence level of 95%. With an estimated one percent of patients lost to follow up, a total of 533 patients will be included.
A clinically relevant difference of more than 5 days in time-to-full recovery between the two treatment strategies is not expected. The liberal strategy without antibiotics and without the strict requirement for hospital admission is anticipated to be more a more cost-effective approach.
Trial registration
Trial registration number: NCT01111253
PMCID: PMC2919453  PMID: 20646266
20.  Costs of relaparotomy on-demand versus planned relaparotomy in patients with severe peritonitis: an economic evaluation within a randomized controlled trial 
Critical Care  2010;14(3):R97.
Results of the first randomized trial comparing on-demand versus planned-relaparotomy strategy in patients with severe peritonitis (RELAP trial) indicated no clear differences in primary outcomes. We now report the full economic evaluation for this trial, including detailed methods, nonmedical costs, further differentiated cost calculations, and robustness of different assumptions in sensitivity analyses.
An economic evaluation was conducted from a societal perspective alongside a randomized controlled trial in 229 patients with severe secondary peritonitis and an acute physiology and chronic health evaluation (APACHE)-II score ≥11 from two academic and five regional teaching hospitals in the Netherlands. After the index laparotomy, patients were randomly allocated to an on-demand or a planned-relaparotomy strategy. Primary resource-utilization data were used to estimate mean total costs per patient during the index admission and after discharge until 1 year after the index operation. Overall differences in costs between the on-demand relaparotomy strategy and the planned strategy, as well as relative differences across several clinical subgroups, were evaluated.
Costs were substantially lower in the on-demand group (mean, €65,768 versus €83,450 per patient in the planned group; mean absolute difference, €17,682; 95% CI, €5,062 to €29,004). Relative differences in mean total costs per patient (approximately 21%) were robust to various alternative assumptions. Planned relaparotomy consistently generated more costs across the whole range of different courses of disease (quick recovery and few resources used on one end of the spectrum; slow recovery and many resources used on the other end). This difference in costs between the two surgical strategies also did not vary significantly across several clinical subgroups.
The reduction in societal costs renders the on-demand strategy a more-efficient relaparotomy strategy in patients with severe peritonitis. These differences were found across the full range of healthcare resources as well as across patients with different courses of disease.
Trial Registration
PMCID: PMC2911734  PMID: 20507557
21.  Polyp measurement based on CT colonography and colonoscopy: variability and systematic differences 
European Radiology  2009;20(6):1404-1413.
To assess the variability and systematic differences in polyp measurements on optical colonoscopy and CT colonography.
Gastroenterologists measured 51 polyps by visual estimation, forceps comparison and linear probe. CT colonography observers randomly assessed polyp size two-dimensionally (abdominal and intermediate window) and three-dimensionally (manually and semi-automatically). Linear mixed models were used to assess the variability and systematic differences between CT colonography and optical colonoscopy techniques.
The variability of forceps and linear probe measurements was comparable and both showed less variability than measurement by visual assessment. Measurements by linear probe were 0.7 mm smaller than measurements by visual assessment or by forceps. The variability of all CT colonography techniques was lower than for measurements by forceps or visual assessment and sometimes lower (only 2D intermediate window and manual 3D) compared with measurements by linear probe. All CT colonography measurements judged polyps to be larger than optical colonoscopy, with differences ranging from 0.7 to 2.3 mm.
A linear probe does not reduce the measurement variability of endoscopists compared with the forceps. Measurement differences between observers on CT colonography were usually smaller than at optical colonoscopy. Polyps appeared larger when using various CT colonography techniques than when measured during optical colonoscopy.
PMCID: PMC2861761  PMID: 20033180
CT colonography; Colon; Colonoscopy; Measurement; Cancer; 2D; 3D
22.  Hyperglycemia in bacterial meningitis: a prospective cohort study 
Hyperglycemia has been associated with unfavorable outcome in several disorders, but few data are available in bacterial meningitis. We assessed the incidence and significance of hyperglycemia in adults with bacterial meningitis.
We collected data prospectively between October 1998 and April 2002, on 696 episodes of community-acquired bacterial meningitis, confirmed by culture of CSF in patients >16 years. Patients were dichotomized according to blood glucose level on admission. A cutoff random non-fasting blood glucose level of 7.8 mmol/L (140 mg/dL) was used to define hyperglycemia, and a cutoff random non-fasting blood glucose level of 11.1 mmol/L (200 mg/dL) was used to define severe hyperglycemia. Unfavorable outcome was defined on the Glasgow outcome scale as a score <5. We also evaluated characteristics of patients with a preadmission diagnosis of diabetes mellitus.
69% of patients were hyperglycemic and 25% severely hyperglycemic on admission. Compared with non-hyperglycemic patients, hyperglycemia was related with advanced age (median, 55 yrs vs. 44 yrs, P < 0.0001), preadmission diagnosis of diabetes (9% vs. 3%, P = 0.005), and distant focus of infection (37% vs. 28%, P = 0.02). They were more often admitted in coma (16% vs. 8%; P = 0.004) and with pneumococcal meningitis (55% vs. 42%, P = 0.007). These differences remained significant after exclusion of patients with known diabetes. Hyperglycemia was related with unfavorable outcome in a univariate analysis but this relation did not remain robust in a multivariate analysis. Factors predictive for neurologic compromise were related with higher blood glucose levels, whereas factors predictive for systemic compromise were related with lower blood glucose levels. Only a minority of severely hyperglycemic patients were known diabetics (19%). The vast majority of these known diabetic patients had meningitis due to Streptococcus pneumoniae (67%) or Listeria monocytogenes (13%) and they were at high risk for unfavorable outcome (52%).
The majority of patients with bacterial meningitis have hyperglycemic blood glucose levels on admission. Hyperglycemia can be explained by a physical stress reaction, the central nervous system insult leading to disturbed blood-glucose regulation mechanisms, and preponderance of diabetics for pneumococcal meningitis. Patients with diabetes and bacterial meningitis are at high risk for unfavorable outcome.
PMCID: PMC2694198  PMID: 19426501
23.  Regional perinatal mortality differences in the Netherlands; care is the question 
BMC Public Health  2009;9:102.
Perinatal mortality is an important indicator of health. European comparisons of perinatal mortality show an unfavourable position for the Netherlands. Our objective was to study regional variation in perinatal mortality within the Netherlands and to identify possible explanatory factors for the found differences.
Our study population comprised of all singleton births (904,003) derived from the Netherlands Perinatal Registry for the period 2000–2004. Perinatal mortality including stillbirth from 22+0 weeks gestation and early neonatal death (0–6 days) was our main outcome measure. Differences in perinatal mortality were calculated between 4 distinct geographical regions North-East-South-West. We tried to explain regional differences by adjustment for the demographic factors maternal age, parity and ethnicity and by socio-economic status and urbanisation degree using logistic modelling. In addition, regional differences in mode of delivery and risk selection were analysed as health care factors. Finally, perinatal mortality was analysed among five distinct clinical risk groups based on the mediating risk factors gestational age and congenital anomalies.
Overall perinatal mortality was 10.1 per 1,000 total births over the period 2000–2004. Perinatal mortality was elevated in the northern region (11.2 per 1,000 total births). Perinatal mortality in the eastern, western and southern region was 10.2, 10.1 and 9.6 per 1,000 total births respectively. Adjustment for demographic factors increased the perinatal mortality risk in the northern region (odds ratio 1.20, 95% CI 1.12–1.28, compared to reference western region), subsequent adjustment for socio-economic status and urbanisation explained a small part of the elevated risk (odds ratio 1.11, 95% CI 1.03–1.20). Risk group analysis showed that regional differences were absent among very preterm births (22+0 – 25+6 weeks gestation) and most prominent among births from 32+0 gestation weeks onwards and among children with severe congenital anomalies. Among term births (≥ 37+0 weeks) regional mortality differences were largest for births in women transferred from low to high risk during delivery.
Regional differences in perinatal mortality exist in the Netherlands. These differences could not be explained by demographic or socio-economic factors, however clinical risk group analysis showed indications for a role of health care factors.
PMCID: PMC2674436  PMID: 19366460
24.  Transanal endoscopic microsurgery versus endoscopic mucosal resection for large rectal adenomas (TREND-study) 
BMC Surgery  2009;9:4.
Recent non-randomized studies suggest that extended endoscopic mucosal resection (EMR) is equally effective in removing large rectal adenomas as transanal endoscopic microsurgery (TEM). If equally effective, EMR might be a more cost-effective approach as this strategy does not require expensive equipment, general anesthesia and hospital admission. Furthermore, EMR appears to be associated with fewer complications.
The aim of this study is to compare the cost-effectiveness and cost-utility of TEM and EMR for the resection of large rectal adenomas.
Multicenter randomized trial among 15 hospitals in the Netherlands. Patients with a rectal adenoma ≥ 3 cm, located between 1–15 cm ab ano, will be randomized to a TEM- or EMR-treatment strategy. For TEM, patients will be treated under general anesthesia, adenomas will be dissected en-bloc by a full-thickness excision, and patients will be admitted to the hospital. For EMR, no or conscious sedation is used, lesions will be resected through the submucosal plane in a piecemeal fashion, and patients will be discharged from the hospital. Residual adenoma that is visible during the first surveillance endoscopy at 3 months will be removed endoscopically in both treatment strategies and is considered as part of the primary treatment.
Primary outcome measure is the proportion of patients with recurrence after 3 months. Secondary outcome measures are: 2) number of days not spent in hospital from initial treatment until 2 years afterwards; 3) major and minor morbidity; 4) disease specific and general quality of life; 5) anorectal function; 6) health care utilization and costs. A cost-effectiveness and cost-utility analysis of EMR against TEM for large rectal adenomas will be performed from a societal perspective with respectively the costs per recurrence free patient and the cost per quality adjusted life year as outcome measures.
Based on comparable recurrence rates for TEM and EMR of 3.3% and considering an upper-limit of 10% for EMR to be non-inferior (beta-error 0.2 and one-sided alpha-error 0.05), 89 patients are needed per group.
The TREND study is the first randomized trial evaluating whether TEM or EMR is more cost-effective for the treatment of large rectal adenomas.
Trial registration number
( NTR1422
PMCID: PMC2664790  PMID: 19284647
25.  Ignoring Dependency between Linking Variables and Its Impact on the Outcome of Probabilistic Record Linkage Studies 
This study sought to examine the differences between ignoring (naïve) and incorporating dependency (nonnaïve) among linkage variables on the outcome of a probabilistic record linkage study.
Design and Measurements
We used the outcomes of a previously developed probabilistic linkage procedure for different registries in perinatal care assuming independence among linkage variables. We estimated the impact of ignoring dependency by re-estimating the linkage weights after constructing a variable that combines the outcomes of the comparison of 2 correlated linking variables. The results of the original naïve and the new nonnaïve strategy were systematically compared for 3 scenarios: the empirical dataset using 9 variables, the empirical dataset using 5 variables, and a simulated dataset using 5 variables.
The linking weight for agreement on 2 correlated variables among nonmatches was estimated considerably higher in the naïve strategy than in the nonnaïve strategy (16.87 vs. 13.55). Therefore, ignoring dependency overestimates the amount of identifying information if both correlated variables agree. The impact on the number of pairs that was classified differently with both approaches was modest in the situation in which there were many different linking variables but grew substantially with fewer variables. The simulation study confirmed the results of the empirical study and suggests that the number of misclassifications can increase substantially by ignoring dependency under less favorable linking conditions.
Dependency often exists between linking variables and has the potential to bias the outcome of a linkage study. The nonnaïve approach is a straightforward method for creating linking weights that accommodate dependency. The impact on the number of misclassifications depends on the quality and number of linking variables relative to the number of correlated linking variables.
PMCID: PMC2528043  PMID: 18579842

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