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G Molenberghs

Publications and source records attributed to G Molenberghs.

At least 19 recordsLinked to original sources
PubMed2003

Geographical differences in cancer incidence in the Belgian province of Limburg.

Correctly addressing the questions of worried citizens with respect to possible clusters of cancer occurrence requires a risk communication strategy that is informed by a previously established analytical procedure. The aim of this study was to analyse cancer registration data in order to identify municipalities or clusters of municipalities with an increased incidence of one or more cancer types, adjusted for background characteristics at the same level. Ideally, the approach is proactive, straightforward, and easy for untrained citizens to follow and imprecision effects are taken into account. For all municipalities and most cancers, all relevant calculations were performed proactively and all methods and decision thresholds were defined beforehand. For each municipality, standardised incidence ratios (SIRs) were calculated and smoothed using a Poisson-gamma (PG) and a conditional autoregressive (CAR) model. Clusters were confirmed using the Spatial scan statistic of Kulldorff. Identified clusters were tested for possible confounders using all information that was available for each municipality. The Limburg Cancer Registry, serving the population of the Belgian province of Limburg (n=781 759) was used. We identified a possible cluster of increased prostate cancer incidence (smoothed SIRs around 1.2) and a cluster of increased bladder cancer incidence in males that included seven municipalities with CAR-smoothed SIRs between 1.5 and 2.1. SIRs followed a more or less circular decrease around the centre that was situated in Alken and Hasselt, the provincial capital. Bladder cancer incidence was positively related to an index of socio-economic status (SES) per municipality. No relationship was found with the other indexes that were available. 82% of all bladder cancers were transitional cell carcinomas (TCC). A repeated analysis based on TCCs only resulted in similar results with CAR-smoothed relative risks that tended to be even higher in the cluster zone. A pre-emptive analysis of possible cancer incidence clustering on the municipality level proved to be feasible.

Belgium↗
PubMed2003

Hepatitis B in St Petersburg, Russia (1994-1999): incidence, prevalence and force of infection.

Hepatitis B (HB) is thought to be an expanding health problem in Russia. The incidence of infection was estimated from mandatorily reported HB cases in St Petersburg. The two-sided t-test for independent samples and the LOESS (locally-weighted regression) smoother were used to compare the age at infection for symptomatic, asymptomatic and chronic infections, by gender. The force of infection was estimated from seroprevalence data (907 sera taken in 1999) using a newly developed nonparametric method based on local polynomials, as well as an earlier method based on isotonic regression and kernel smoothers. With the local polynomial method, pointwise confidence intervals (95%) were constructed by bootstrapping. On average, men contracted HB infection at a significantly younger age than women (in 1999, 21.8 vs 22.7 years, respectively). The overall male to female ratio was 1.92. In 1999 the overall incidence almost doubled compared with the preceding years and tripled among the age groups with highest incidence (15-29-year olds: 85% of cases in 1999). The incidence increase was associated with a lower average age at infection (24.1 years in 1994 vs 22.1 years in 1999). The age and gender-specific force of infection estimates generally confirmed the incidence estimates and emphasized the usefulness of local polynomials to do this. Hence HB transmission in St Petersburg occurs mainly in young adults. The dramatic increase of infections in 1999 was probably due to injecting drug use. Without intervention, HB virus is expected to continue to spread rapidly with a greater proportion of female infections caused by sexual transmission. These trends may also provide an indication for HIV transmission.

Adolescent↗
PubMed2002

Prostate-specific antigen screening coverage and prostate cancer incidence rates in the Belgian province of Limburg in 1996-1998.

According to the 1996-1998 cancer incidence report of the cancer registry of the Belgian province of Limburg (LIKAR), prostate cancer is the most common cancer in men with a crude invasive cancer incidence rate of 123.7 per 100000 person-years (125.4 and 81.8 after standardization for the European and the world standard population). In a study on geographical differences between the occurrence of cancers in municipalities, prostate cancer standardized incidence rates (SIRs) were significantly higher in a number of municipalities, with mean relative risks of 1.2 and 1.3 after full Bayesian smoothing. We hypothesized that prostate cancer incidence rates are largely influenced by the prostate-specific antigen (PSA) screening policy of local physicians and that differences between municipalities are more informative about local screening habits then about real differences in cancer occurrence. The aim of this study was to test this hypothesis by relating local prostate cancer SIRs to the PSA screening coverage of the population of men in each municipality. The SIRs of prostate cancer in 1996-1998 for each municipality were provided by LIKAR. They related to all histologically or cytologically proven new invasive prostate cancers during these years. For each municipality, PSA coverage data were provided by the largest sick fund of the region. Coverage was defined as the proportion of men above the age of 40 that was tested at least once within the registration period. The SIR of each municipality (dependent variable) was related to the age-standardized corresponding coverage (independent variable) by linear regression and was adjusted for the number of inhabitants per municipality: log (standardized incidence rate) = 164 + 602 * (standardized PSA coverage), = 0.12. The model explained 6% of the variance in incidence. In conclusion, in this study no statistically significant relationship was identified between PSA coverage and prostate cancer incidence rate per municipality. This could result from no such relationship existing or from low statistical power.

Adult↗
PubMed2002

Analysing longitudinal continuous quality of life data with dropout.

Quality of Life (QL) is becoming an increasingly popular endpoint in phase III cancer clinical trials. However, there is still no agreement as to what is the optimal approach to analysis. In this paper we review some concepts which should be considered during a QL analysis. We present two modelling approaches that have been substantively developed in other research fields: selection models and pattern-mixture models. These models are compared using data from an EORTC clinical trial in poor-prognosis prostate cancer patients. It is illustrated that, although selection models and pattern mixture are probabilistically equivalent, they may shed completely different light on data from a modeller's point of view.

Clinical Trials, Phase III as Topic↗
PubMed2001

Sensitivity analysis of longitudinal binary quality of life data with drop-out: an example using the EORTC QLQ-C30.

Analysing quality of life data (QOL) may be complicated for several reasons. Quality of life data not only involves repeated measures but is also usually collected on ordered categorical responses. In addition, it is evident that not all patients provide the same number of assessments, due to attrition caused by death or other medical reasons. In the recent statistical literature, increasing attention is given to methods which can handle non-continuous outcomes in the presence of missing data. The aim of this paper is to investigate the effect on statistical conclusions of applying different modelling techniques to QOL data generated from an EORTC phase III trial. Treatment effects and treatment differences are of major concern. First, a random-effects model is fitted, relating a binary longitudinal response (derived from the physical functioning scale of the QLQ-C30) to several covariates. In a second approach, marginal models are fitted, retaining the response variable and the mean structure used before. The fitted marginal models only differ with respect to the considered estimation procedure: generalized estimating equations (GEE); weighted generalized estimating equations (WGEE), and maximum likelihood (ML).

Antibiotics, Antineoplastic↗
PubMed2001

Evaluation of surrogate endpoints in randomized experiments with mixed discrete and continuous outcomes.

A statistical definition of surrogate endpoints as well as validation criteria was first presented by Prentice. Freedman et al. supplemented these criteria with the so-called proportion explained. Buyse and Molenberghs pointed to inadequacies of these criteria and suggested a new definition of surrogacy based on (i) the relative effect linking the overall effect of treatment on both endpoints and (ii) an individual-level measure of agreement between both endpoints. Using data from a randomized trial, they showed how a potential surrogate endpoint can be studied using a joint model for the surrogate and the true endpoint. Whereas Buyse and Molenberghs restricted themselves to the fairly simple cases of jointly normal and jointly binary outcomes, we treat the situation where the surrogate is binary and the true endpoint is continuous, or vice versa. In addition, we consider the case of ordinal endpoints. Further, Buyse et al. extended the approach of Buyse and Molenberghs to a meta-analytic context. We will adopt a similar approach for responses of a mixed data type.

Anticholesteremic Agents↗
PubMed2001

Modelling bivariate ordinal responses smoothly with examples from ophthalmology and genetics.

A non-parametric implementation of the bivariate Dale model (BDM) is presented as an extension of the generalized additive model (GAM) of Hastie and Tibshirani. The original BDM is an example of a bivariate generalized linear model. In this paper smoothing is introduced on the marginal as well as on the association level. Our non-parametric procedure can be used as a diagnostic tool for identifying parametric transformations of the covariates in the linear BDM, hence it also provides a kind of goodness-of-fit test for a bivariate generalized linear model. Cubic smoothing spline functions for the covariates are estimated by maximizing a penalized version of the log-likelihood. The method is applied to two studies. The first study is the classical Wisconsin Epidemiologic Study of Diabetic Retinopathy. The second study is a twin study, where the association between the elements of twin pairs is of primary interest. The results show that smoothing on the association level can give a significant improvement to the model fit.

Adolescent↗
PubMed2001

Sexual dysfunction associated with protease inhibitor containing highly active antiretroviral treatment.

BACKGROUND: A high proportion of individuals receiving highly active antiretroviral treatment (HAART) complain of sexual dysfunction (SD), encompassing a lack of desire or erectile dysfunction. OBJECTIVE: To determine whether SD was associated with particular components of the HAART regimens and to identify risk factors for the development of SD in patients on HAART. METHODS: A survey among patients with HIV infection using an anonymous questionnaire was conducted in 10 European countries between December 1998 and December 1999. A total of 904 individuals currently receiving antiretroviral agents were included in the analyses. RESULTS: A decrease in sexual interest was significantly more frequently reported by subjects (men and women) using HAART containing protease inhibitors (PI) (308/766, 40%), compared with PI-naive patients (22/138, 16%; OR 3.55; 95% CI 2.15--5.89). In addition, a significantly larger number of PI-experienced men reported a decrease in sexual potency (216/628, 34%) compared with PI-naive men (12/99, 12%; OR 2.56; 95% CI 1.33--5.03). In multivariate analyses the following factors were associated with a decrease in sexual interest: a current PI-containing regimen, a history of a PI regimen, symptomatic HIV infection, age and homosexual contact as HIV transmission mode. Factors associated with a decrease in sexual potency were: current use of a PI-containing regimen, symptomatic HIV disease, age and the use of tranquillisers. CONCLUSION: SD appears to be a common side-effect of HAART regimens containing a PI. The potential association between SD and other side-effects of HAART, such as lipodystrophy syndrome and neuropathy, should be investigated further.

Adult↗
PubMed2001

Repeated-measures models to evaluate a hepatitis B vaccination programme.

In 1985-1986, a hepatitis B vaccination programme was conducted in a Belgian institution for the mentally handicapped. A group of 97 residents was followed up for 11 years in order to characterize the long-term persistence of hepatitis B antibodies after vaccination. This paper proposes the use of linear mixed-effects models to account for serial correlation and between-individual heterogeneity in the data, while adjusting the analysis for various individual characteristics and important risk factors in the response to vaccination. We propose several model building strategies and focus on the prediction of future levels of antibodies.

Belgium↗
PubMed2001

Testing for bias in weighted estimating equations.

It is very common in regression analysis to encounter incompletely observed covariate information. A recent approach to analyse such data is weighted estimating equations (Robins, J. M., Rotnitzky, A. and Zhao, L. P. (1994), JASA, 89, 846-866, and Zhao, L. P., Lipsitz, S. R. and Lew, D. (1996), Biometrics, 52, 1165-1182). With weighted estimating equations, the contribution to the estimating equation from a complete observation is weighted by the inverse of the probability of being observed. We propose a test statistic to assess if the weighted estimating equations produce biased estimates. Our test statistic is similar to the test statistic proposed by DuMouchel and Duncan (1983) for weighted least squares estimates for sample survey data. The method is illustrated using data from a randomized clinical trial on chemotherapy for multiple myeloma.

Journal Article↗
PubMed2001

Pesticides and mortality from hormone-dependent cancers.

Endocrine-disrupting chemicals are considered to be a possible cause of hormone-dependent cancers. In areas of high exposure to pesticides, people are concerned about the long lasting toxicity of pesticides, some of which are possibly hormonally active. We collected for each Belgian municipality (n = 589) the latest mortality statistics from breast and prostate cancer (period 1985-1994) and the latest data on crops and pesticides (1998). In addition, data on possible confounders such as population density, degree of urbanization, industrial activity and the presence of an incinerator were collected as well. The data were analysed with spatial statistics that takes into account the spatial nature of the data. There is a large variation in crops and pesticide exposure among the municipalities, the highest exposure being seen in the fruit production area. Apart from use of defoliants and potato cultivation, no consistent correlation was detected between crops, pesticides and mortality from breast and prostate cancer. Our data cannot support the hypothesis of a relationship between total and class-related pesticide use and breast and prostate cancer mortality. However, the increased mortality due to breast cancer and to a lesser extent due to prostate cancer in traditional potato-growing areas needs attention and more research.

Belgium↗
PubMed2001

Sensitivity analysis for nonrandom dropout: a local influence approach.

Diggle and Kenward (1994, Applied Statistics 43, 49-93) proposed a selection model for continuous longitudinal data subject to nonrandom dropout. It has provoked a large debate about the role for such models. The original enthusiasm was followed by skepticism about the strong but untestable assumptions on which this type of model invariably rests. Since then, the view has emerged that these models should ideally be made part of a sensitivity analysis. This paper presents a formal and flexible approach to such a sensitivity assessment based on local influence (Cook, 1986, Journal of the Royal Statistical Society, Series B 48, 133-169). The influence of perturbing a missing-at-random dropout model in the direction of nonrandom dropout is explored. The method is applied to data from a randomized experiment on the inhibition of testosterone production in rats.

Animals↗
PubMed2001

Bias in estimating association parameters for longitudinal binary responses with drop-outs.

This paper considers the impact of bias in the estimation of the association parameters for longitudinal binary responses when there are drop-outs. A number of different estimating equation approaches are considered for the case where drop-out cannot be assumed to be a completely random process. In particular, standard generalized estimating equations (GEE), GEE based on conditional residuals, GEE based on multivariate normal estimating equations for the covariance matrix, and second-order estimating equations (GEE2) are examined. These different GEE estimators are compared in terms of finite sample and asymptotic bias under a variety of drop-out processes. Finally, the relationship between bias in the estimation of the association parameters and bias in the estimation of the mean parameters is explored.

Algorithms↗
PubMed2001

An exact trend test for correlated binary data.

The problem of testing a dose-response relationship in the presence of exchangeably correlated binary data has been addressed using a variety of models. Most commonly used approaches are derived from likelihood or generalized estimating equations and rely on large-sample theory to justify their inferences. However, while earlier work has determined that these methods may perform poorly for small or sparse samples, there are few alternatives available to those faced with such data. We propose an exact trend test for exchangeably correlated binary data when groups of correlated observations are ordered. This exact approach is based on an exponential model derived by Molenberghs and Ryan (1999) and Ryan and Molenberghs (1999) and provides natural analogues to Fisher's exact test and the binomial trend test when the data are correlated. We use a graphical method with which one can efficiently compute the exact tail distribution and apply the test to two examples.

Abnormalities, Drug-Induced↗
PubMed2000

Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Meta-Analysis Group in Cancer.

BACKGROUND: Treatment of advanced colorectal cancer has progressed substantially. However, improvements in response rates have not always translated into significant survival benefits. Doubts have therefore been raised about the usefulness of tumour response as a clinical endpoint. METHODS: This meta-analysis was done on individual data from 3791 patients enrolled in 25 randomised trials of first-line treatment with standard bolus intravenous fluoropyrimidines versus experimental treatments (fluorouracil plus leucovorin, fluorouracil plus methotrexate, fluorouracil continuous infusion, or hepatic-arterial infusion of floxuridine). Analyses were by intention to treat. FINDINGS: Compared with bolus fluoropyrimidines, experimental fluoropyrimidines led to significantly higher tumour response rates (454 responses among 2031 patients vs 209 among 1760; odds ratio 0.48 [95% CI 0.40-0.57], p<0.0001) and better survival (1808 deaths among 2031 vs 1580 among 1760; hazard ratio 0.90 [0.84-0.97], p=0.003). The survival benefits could be explained by the higher tumour response rates. However, a treatment that lowered the odds of failure to respond by 50% would be expected to decrease the odds of death by only 6%. In addition, less than half of the variability of the survival benefits in the 25 trials could be explained by the variability of the response benefits in these trials. INTERPRETATION: These analyses confirm that an increase in tumour response rate translates into an increase in overall survival for patients with advanced colorectal cancer. However, in the context of individual trials, knowledge that a treatment has benefits on tumour response does not allow accurate prediction of the ultimate benefit on survival.

Antimetabolites, Antineoplastic↗
PubMed2000

Summary measures and statistics in the analysis of quality of life data: an example from an EORTC-NCIC-SAKK locally advanced breast cancer study.

Quality of Life (QL) is now included as an endpoint in many phase III cancer clinical trials. Numerous statistical techniques have been presented in the literature to analyse QL data but there is still no agreement as to what is the optimal approach of analysis. In this paper we, therefore, present and compare various techniques which have all appeared in the literature and which may be globally described as summary measures and summary statistics. These techniques are illustrated using data from an EORTC clinical trial in locally advanced breast cancer (EORTC trial 10921). It is also explained in this paper how and when these techniques may be used in other cancer settings. For EORTC trial 10921, it is shown that by choosing different techniques different conclusions may be drawn concerning the QL outcome. This highlights the importance of choosing an appropriate primary statistical method and for describing it a priori in the protocol and analysis plan. In this paper, we show the importance of performing sensitivity or supportive analysis to support conclusions drawn from the primary analysis.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

The dysphonia severity index: an objective measure of vocal quality based on a multiparameter approach.

The vocal quality of a patient is modeled by means of a Dysphonia Severity Index (DSI), which is designed to establish an objective and quantitative correlate of the perceived vocal quality. The DSI is based on the weighted combination of the following selected set of voice measurements: highest frequency (F(0)-High in Hz), lowest intensity (I-Low in dB), maximum phonation time (MPT in s), and jitter (%). The DSI is derived from a multivariate analysis of 387 subjects with the goal of describing, purely based on objective measures, the perceived voice quality. It is constructed as DSI = 0.13 x MPT + 0.0053 x F(0)-High - 0.26 x I-Low - 1.18 x Jitter (%) + 12.4. The DSI for perceptually normal voices equals +5 and for severely dysphonic voices -5. The more negative the patient's index, the worse is his or her vocal quality. As such, the DSI is especially useful to evaluate therapeutic evolution of dysphonic patients. Additionally, there is a high correlation between the DSI and the Voice Handicap Index score.

Adolescent↗