Hendrik Koffijberg

Common Carotid Intima-Media Thickness Measurements in Cardiovascular Risk Prediction: A Meta-analysis

CONTEXT The evidence that measurement of the common carotid intima-media thickness (CIMT) improves the risk scores in prediction of the absolute risk of cardiovascular events is inconsistent. OBJECTIVE To determine whether common CIMT has added value in 10-year risk prediction of first-time myocardial infarctions or strokes, above that of the Framingham Risk Score. DATA SOURCES Relevant studies were identified through literature searches of databases (PubMed from 1950 to June 2012 and EMBASE from 1980 to June 2012) and expert opinion. STUDY SELECTION Studies were included if participants were drawn from the general population, common CIMT was measured at baseline, and individuals were followed up for first-time myocardial infarction or stroke. DATA EXTRACTION Individual data were combined into 1 data set and an individual participant data meta-analysis was performed on individuals without existing cardiovascular disease. RESULTS We included 14 population-based cohorts contributing data for 45,828 individuals. During a median follow-up of 11 years, 4007 first-time myocardial infarctions or strokes occurred. We first refitted the risk factors of the Framingham Risk Score and then extended the model with common CIMT measurements to estimate the absolute 10-year risks to develop a first-time myocardial infarction or stroke in both models. The C statistic of both models was similar (0.757; 95% CI, 0.749-0.764; and 0.759; 95% CI, 0.752-0.766). The net reclassification improvement with the addition of common CIMT was small (0.8%; 95% CI, 0.1%-1.6%). In those at intermediate risk, the net reclassification improvement was 3.6% in all individuals (95% CI, 2.7%-4.6%) and no differences between men and women. CONCLUSION The addition of common CIMT measurements to the Framingham Risk Score was associated with small improvement in 10-year risk prediction of first-time myocardial infarction or stroke, but this improvement is unlikely to be of clinical importance.

Subarachnoid haemorrhage in Sweden 1987-2002: regional incidence and case fatality rates

Background: Incidence estimates of subarachnoid haemorrhage (SAH) in Sweden vary, which may be caused by regional variations. Reliable estimates of age-specific case fatality rates are lacking. We analysed regional incidence rates and case fatality rates of SAH in Sweden. Methods: The Swedish Hospital Discharge and Cause of Death Registries from 1987 to 2002 yielded data on 18 443 patients with SAH. Incidence and case fatality rates by age, gender, region and time period were calculated by Poisson regression. Results: The incidence rate was 12.4 per 100 000 person-years (95% CI 12.2 to 12.6) and increased with age, from 6.4/100 000 person-years in patients who were 30–39 years old to 25.8/100 000 person-years in patients who were older than 80 years. Incidence was higher for women (14.4 (95% CI 14.2 to 14.7)) than for men (10.3 (95% CI 10.3 to 10.6)), and higher in the north than in the south (RR 1.31 (95% CI 1.25 to 1.37)). This geographical gradient was more evident in women (RR 1.41 (95% CI 1.33 to1.49)) than in men (RR 1.23 (95% CI 1.15 to 1.33)). The 28-day case fatality rate was 31.7% (95% CI 31.0 to 32.3). It increased with age from 18.1% (95% CI 16.0 to 20.3) in patients who were 30–39 years old to 57.6% (95% CI 55.2 to 59.9) in patients over 80 years, then levelling off. Over time (1995–2002 compared with 1987–1994), the incidence rate decreased (RR 0.93 (95% CI 0.90 to 0.96)) and case fatality rate decreased (RR 0.89 (95% CI 0.85 to 0.93)). Conclusions: SAH incidence rates in Sweden increase from south to north, more in women than in men. Octogenarians have a quadrupled incidence and a tripled case fatality compared with young adults. During 16 years, both incidence and case fatality have decreased.

Robot-assisted minimally invasive thoraco-laparoscopic esophagectomy versus open transthoracic esophagectomy for resectable esophageal cancer, a randomized controlled trial (ROBOT trial)

BackgroundFor esophageal cancer patients, radical esophagolymphadenectomy is the cornerstone of multimodality treatment with curative intent. Transthoracic esophagectomy is the preferred surgical approach worldwide allowing for en-bloc resection of the tumor with the surrounding lymph nodes. However, the percentage of cardiopulmonary complications associated with the transthoracic approach is high (50 to 70%).Recent studies have shown that robot-assisted minimally invasive thoraco-laparoscopic esophagectomy (RATE) is at least equivalent to the open transthoracic approach for esophageal cancer in terms of short-term oncological outcomes. RATE was accompanied with reduced blood loss, shorter ICU stay and improved lymph node retrieval compared with open esophagectomy, and the pulmonary complication rate, hospital stay and perioperative mortality were comparable. The objective is to evaluate the efficacy, risks, quality of life and cost-effectiveness of RATE as an alternative to open transthoracic esophagectomy for treatment of esophageal cancer.Methods/designThis is an investigator-initiated and investigator-driven monocenter randomized controlled parallel-group, superiority trial. All adult patients (age ≥18 and ≤80 years) with histologically proven, surgically resectable (cT1-4a, N0-3, M0) esophageal carcinoma of the intrathoracic esophagus and with European Clinical Oncology Group performance status 0, 1 or 2 will be assessed for eligibility and included after obtaining informed consent. Patients (n = 112) with resectable esophageal cancer are randomized in the outpatient department to either RATE (n = 56) or open three-stage transthoracic esophageal resection (n = 56). The primary outcome of this study is the percentage of overall complications (grade 2 and higher) as stated by the modified Clavien–Dindo classification of surgical complications.DiscussionThis is the first randomized controlled trial designed to compare RATE with open transthoracic esophagectomy as surgical treatment for resectable esophageal cancer. If our hypothesis is proven correct, RATE will result in a lower percentage of postoperative complications, lower blood loss, and shorter hospital stay, but with at least similar oncologic outcomes and better postoperative quality of life compared with open transthoracic esophagectomy. The study started in January 2012. Follow-up will be 5 years. Short-term results will be analyzed and published after discharge of the last randomized patient.Trial registrationDutch trial register: NTR3291 ClinicalTrial.gov: NCT01544790

Individual Participant Data Meta-Analysis for a Binary Outcome: One-Stage or Two-Stage?

Background A fundamental aspect of epidemiological studies concerns the estimation of factor-outcome associations to identify risk factors, prognostic factors and potential causal factors. Because reliable estimates for these associations are important, there is a growing interest in methods for combining the results from multiple studies in individual participant data meta-analyses (IPD-MA). When there is substantial heterogeneity across studies, various random-effects meta-analysis models are possible that employ a one-stage or two-stage method. These are generally thought to produce similar results, but empirical comparisons are few. Objective We describe and compare several one- and two-stage random-effects IPD-MA methods for estimating factor-outcome associations from multiple risk-factor or predictor finding studies with a binary outcome. One-stage methods use the IPD of each study and meta-analyse using the exact binomial distribution, whereas two-stage methods reduce evidence to the aggregated level (e.g. odds ratios) and then meta-analyse assuming approximate normality. We compare the methods in an empirical dataset for unadjusted and adjusted risk-factor estimates. Results Though often similar, on occasion the one-stage and two-stage methods provide different parameter estimates and different conclusions. For example, the effect of erythema and its statistical significance was different for a one-stage (OR = 1.35, ) and univariate two-stage (OR = 1.55, ). Estimation issues can also arise: two-stage models suffer unstable estimates when zero cell counts occur and one-stage models do not always converge. Conclusion When planning an IPD-MA, the choice and implementation (e.g. univariate or multivariate) of a one-stage or two-stage method should be prespecified in the protocol as occasionally they lead to different conclusions about which factors are associated with outcome. Though both approaches can suffer from estimation challenges, we recommend employing the one-stage method, as it uses a more exact statistical approach and accounts for parameter correlation.

A framework for developing, implementing, and evaluating clinical prediction models in an individual participant data meta-analysis

The use of individual participant data (IPD) from multiple studies is an increasingly popular approach when developing a multivariable risk prediction model. Corresponding datasets, however, typically differ in important aspects, such as baseline risk. This has driven the adoption of meta-analytical approaches for appropriately dealing with heterogeneity between study populations. Although these approaches provide an averaged prediction model across all studies, little guidance exists about how to apply or validate this model to new individuals or study populations outside the derivation data. We consider several approaches to develop a multivariable logistic regression model from an IPD meta-analysis (IPD-MA) with potential between-study heterogeneity. We also propose strategies for choosing a valid model intercept for when the model is to be validated or applied to new individuals or study populations. These strategies can be implemented by the IPD-MA developers or future model validators. Finally, we show how model generalizability can be evaluated when external validation data are lacking using internal-external cross-validation and extend our framework to count and time-to-event data. In an empirical evaluation, our results show how stratified estimation allows study-specific model intercepts, which can then inform the intercept to be used when applying the model in practice, even to a population not represented by included studies. In summary, our framework allows the development (through stratified estimation), implementation in new individuals (through focused intercept choice), and evaluation (through internal-external validation) of a single, integrated prediction model from an IPD-MA in order to achieve improved model performance and generalizability.

Growth rates of intracranial aneurysms: exploring constancy

OBJECT The annual rate of rupture of intracranial aneurysms is often assumed to be constant, but it is unknown whether this assumption is true. Recent case reports have suggested that aneurysms grow fast in a short period of time. The authors of the present report investigated the plausibility of a constant growth rate for intracranial aneurysms. METHODS Assuming a constant aneurysm growth rate within an individual and varying rates between individuals, a hypothetical cohort was simulated. Individuals with high growth rates will display aneurysm formation and rupture at a young age; such persons disappear early from the hypothetical cohort. As a result the mean lesion growth rate varies over time. In hypothetical cohorts with different initial mean growth rates, the authors calculated age-specific incidence rates (per 100,000 person-years) of subarachnoid hemorrhage and compared these rates with population-based data on the incidence of subarachnoid hemorrhage (per 100,000 person-years). RESULTS A hypothetical cohort with a mean initial growth rate of 0.18 mm/year reproduced most closely the incidence rates observed in the population. However, even for this most plausible hypothetical cohort, age-specific incidence rates in the model differed substantially and statistically significantly from those observed in the population. CONCLUSIONS Based on the results of this study, it is unlikely that intracranial aneurysms in general grow at a constant time-independent rate. The authors hypothesized that the actual growth process is irregular and discontinuous, which results in periods with and without aneurysm growth and with high and low risks of rupture.

Optimal screening strategy for familial intracranial aneurysms: A cost-effectiveness analysis

Objective: Individuals with a family history of subarachnoid hemorrhage (SAH), defined as 2 or more affected first-degree relatives, have an increased risk of aneurysm formation and rupture. Screening such individuals for intracranial aneurysms is advocated, but its effectiveness and cost-effectiveness are unknown, as are the optimal age ranges and interval for screening. Methods: With a Markov model and Monte Carlo simulations we compared screening with no screening in individuals with a family history of SAH. We varied age ranges (starting screening at 20, 30, or 40 years old, ending screening at 60, 70, or 80 years old) and screening intervals (2-, 3-, 5-, 7-, 10-, and 15-year interval), and analyzed the impact in costs and quality-adjusted life years (QALY). Results: Screening individuals with a family history of SAH is cost-effective. The strategy with the lowest costs per QALY was to screen only twice, at 40 and 55 years old. Sequentially lengthening the screening period and decreasing the screening interval yielded additional health benefits at acceptable costs up to screening from age 20 to 80 every 7 years. More frequent screening within this age range still provided extra QALYs, with an incremental cost-effectiveness ratio more favorable than 26,308/QALY (

Multiple imputation of missing repeated outcome measurements did not add to linear mixed-effects models

38,410/QALY). Conclusion: This study provides evidence for recommendations to screen individuals with 2 or more first-degree relatives with subarachnoid hemorrhage. The optimal screening strategy according to our model is screening from age 20 until 80 every 7 years given a cost-effectiveness threshold of 20,000/quality-adjusted life year (QALY) (

Markers for the non-invasive diagnosis of mesothelioma: a systematic review

29,200/QALY).

Risk of subarachnoid haemorrhage according to number of affected relatives: a population based case-control study

OBJECTIVE To assess the added value of multiple imputation (MI) of missing repeated outcomes measures in longitudinal data sets analyzed with linear mixed-effects (LME) models. STUDY DESIGN AND SETTING Data were used from a trial on the effects of Rosuvastatin on rate of change in carotid intima-media thickness (CIMT). The reference treatment effect was derived from a complete data set. Scenarios and proportions of missing values in CIMT measurements were applied and LME analyses were used before and after MI. The added value of MI, in terms of bias and precision, was assessed using the mean-squared error (MSE) of the treatment effects and coverage of the 95% confidence interval. RESULTS The reference treatment effect was -0.0177 mm/y. The MSEs for LME analysis without and with MI were similar in scenarios with up to 40% missing values. Coverage was large in all scenarios and was similar for LME with and without MI. CONCLUSION Our study empirically shows that MI of missing end point data before LME analyses does not increase precision in the estimated rate of change in the end point. Hence, MI had no added value in this setting and standard LME modeling remains the method of choice.