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Geert Molenberghs

Publications and source records attributed to Geert Molenberghs.

At least 37 records · Page 2Linked to original sources
PubMed2004

Applying linear mixed models to estimate reliability in clinical trial data with repeated measurements.

Repeated measures are exploited to study reliability in the context of psychiatric health sciences. It is shown how test-retest reliability can be derived using linear mixed models when the scale is continuous or quasi-continuous. The advantage of this approach is that the full modeling power of mixed models can be used. Repeated measures with a different mean structure can be used to usefully study reliability, correction for covariate effects is possible, and a complicated variance-covariance structure between measurements is allowed. In case the variance structure reduces to a random intercept (compound symmetry), classical methods are recovered. With more complex variance structures (e.g., including random slopes of time and/or serial correlation), time-dependent reliability functions are obtained. The methodology is motivated by and applied to data from five double-blind randomized clinical trials comparing the effects of risperidone to conventional antipsychotic agents for the treatment of chronic schizophrenia. Model assumptions are investigated through residual plots and by investigating the effect of influential observations.

Analysis of Variance↗
PubMed2004

Sensitivity analysis for pattern mixture models.

Incomplete series of data is a common feature in quality-of-life studies, in particular in chronic diseases where attrition of patients is high. Two alternative approaches to modeling longitudinal data with incomplete measurements have frequently been proposed in the literature, selection models and pattern-mixture models. In this paper we focus on, by way of sensitivity analysis, extrapolating incomplete patterns using identifying restrictions. Perhaps the best known ones are so-called complete case missing value restrictions (CCMV), where for a given pattern, the conditional distribution of the missing data, given the observed data, is equated to its counterpart in the completers. Available case missing value (ACMV) restrictions equate this conditional density to the one calculated from the subgroup of all patterns for which all required components have been observed. Neighboring case missing value restrictions (NCMV) equate this conditional density to the one calculated from the the pattern with one additional measurement obtained. In this paper, these three identifying restriction strategies are used to multiply impute missing data in a study in metastatic prostate cancer. Multiple imputation is employed to reduce the uncertainty of single imputation. It is shown how hypothesis testing and sensitivity analyses are carried out in this setting.

Humans↗
PubMed2004

Analyzing incomplete longitudinal clinical trial data.

Using standard missing data taxonomy, due to Rubin and co-workers, and simple algebraic derivations, it is argued that some simple but commonly used methods to handle incomplete longitudinal clinical trial data, such as complete case analyses and methods based on last observation carried forward, require restrictive assumptions and stand on a weaker theoretical foundation than likelihood-based methods developed under the missing at random (MAR) framework. Given the availability of flexible software for analyzing longitudinal sequences of unequal length, implementation of likelihood-based MAR analyses is not limited by computational considerations. While such analyses are valid under the comparatively weak assumption of MAR, the possibility of data missing not at random (MNAR) is difficult to rule out. It is argued, however, that MNAR analyses are, themselves, surrounded with problems and therefore, rather than ignoring MNAR analyses altogether or blindly shifting to them, their optimal place is within sensitivity analysis. The concepts developed here are illustrated using data from three clinical trials, where it is shown that the analysis method may have an impact on the conclusions of the study.

Antidepressive Agents↗
PubMed2004

Prentice's approach and the meta-analytic paradigm: a reflection on the role of statistics in the evaluation of surrogate endpoints.

We put a perspective on the strengths and limitations of statistical methods for the evaluation of surrogate endpoints. Whereas using several trials overcomes some of the limitations of a single-trial framework (Prentice, 1989, Statistics in Medicine 8, 431-440), arguably the evaluation of surrogate endpoints can never be done using only statistical evidence but such evidence should be seen as but one component in a decision-making process that involves, among others, a number of clinical and biological considerations. We briefly present a hierarchical framework that incorporates ideas from Prentice's work and is uniformly applicable to different types of surrogate and true clinical outcomes.

Biometry↗
PubMed2004

Validation of surrogate markers in multiple randomized clinical trials with repeated measurements: canonical correlation approach.

Part of the recent literature on the evaluation of biomarkers as surrogate endpoints starts from a multitrial context, which leads to a definition of validity in terms of the quality of both trial-level and individual-level association between the surrogate and true endpoints (Buyse et al., 2000, Biostatistics1, 49-67). These authors concentrated on cross-sectional continuous responses. However, in many randomized clinical studies, repeated measurements are encountered on either or both endpoints. A challenge in this setting is the formulation of a simple and meaningful concept of "surrogacy."Alonso et al. (2003, Biometrical Journal45, 931-945) proposed the variance reduction factor (VRF) to evaluate surrogacy at the individual level. They also showed how and when this concept should be extended to study surrogacy at the trial level. Here, we approach the problem from the natural canonical correlation perspective. We define a class of canonical correlation functions that can be used to study surrogacy at the trial and individual level. We show that the VRF and the R2 measure defined by Buyse et al. (2000) follow as special cases. Simulations are conducted to evaluate the performance of different members of this family. The methodology is illustrated on data from a meta-analysis of five clinical trials comparing antipsychotic agents for the treatment of chronic schizophrenia.

Antipsychotic Agents↗
PubMed2004

A perspective on surrogate endpoints in controlled clinical trials.

The last couple of decades have seen a large amount of activity in the area of surrogate marker and surrogate endpoint validation, both from a clinical and a statistical perspective. Prentice made a pivotal contribution in the context of a single trial. Subsequently, the framework he proposed has been discussed, criticized, and extended. An important class of extensions considers several rather than a single trial. Recently, a lot of work has been done in this so-called hierarchical or meta-analytic framework. In this paper, we review both the single trial and the hierarchical framework. A number of applications, scattered throughout the literature, are brought together. We outline the statistical issues involved in trying to validate surrogate endpoints. Clearly statistical evidence should only be seen as a component in a decision making process that also involves a number of clinical and biological considerations.

Antineoplastic Agents, Hormonal↗
PubMed2004

The effect of correlation structure on treatment contrasts estimated from incomplete clinical trial data with likelihood-based repeated measures compared with last observation carried forward ANOVA.

Valid analyses of longitudinal data can be problematic, particularly when subjects dropout prior to completing the trial for reasons related to the outcome. Regulatory agencies often favor the last observation carried forward (LOCF) approach for imputing missing values in the primary analysis of clinical trials. However, recent evidence suggests that likelihood-based analyses developed under the missing at random framework provide viable alternatives. The within-subject error correlation structure is often the means by which such methods account for the bias from missing data. The objective of this study was to extend previous work that used only one correlation structure by including several common correlation structures in order to assess the effect of the correlation structure in the data, and how it is modeled, on Type I error rates and power from a likelihood-based repeated measures analysis (MMRM), using LOCF for comparison. Data from four realistic clinical trial scenarios were simulated using autoregressive, compound symmetric and unstructured correlation structures. When the correct correlation structure was fit, MMRM provided better control of Type I error and power than LOCF. Although misfitting the correlation structure in MMRM inflated Type I error and altered power, misfitting the structure was typically less deleterious than using LOCF. In fact, simply specifying an unstructured matrix for use in MMRM, regardless of the true correlation structure, yielded superior control of Type I error than LOCF in every scenario. The present and previous investigations have shown that the bias in LOCF is influenced by several factors and interactions between them. Hence, it is difficult to precisely anticipate the direction and magnitude of bias from LOCF in practical situations. However, in scenarios where the overall tendency is for patient improvement, LOCF tends to: 1) overestimate a drug's advantage when dropout is higher in the comparator and underestimate the advantage when dropout is lower in the comparator; 2) overestimate a drug's advantage when the advantage is maximum at intermediate time points and underestimate the advantage when the advantage increases over time; and 3) have a greater likelihood of overestimating a drug's advantage when the advantage is small. In scenarios in which the overall tendency is for patient worsening, the above biases are reversed. In the simulation scenarios considered in this study, which were patterned after acute phase neuropsychiatric clinical trials, the likelihood-based repeated measures approach, implemented with standard software, was more robust to the bias from missing data than LOCF, and choice of correlation structure was not an impediment to its implementation.

Analysis of Variance↗
PubMed2003

Assessing and interpreting treatment effects in longitudinal clinical trials with missing data.

Treatment effects are often evaluated by comparing change over time in outcome measures; however, valid analyses of longitudinal data can be problematic, particularly if some data are missing. For decades, the last observation carried forward (LOCF) approach has been a common method of handling missing data. Considerable advances in statistical methodology and our ability to implement those methods have been made in recent years. Thus, it is appropriate to reconsider analytic approaches for longitudinal data. This review examines the following from a clinical perspective: 1) the characteristics of missing data that influence analytic choices; 2) the attributes of common methods of handling missing data; and 3) the use of the data characteristics and the attributes of the various methods, along with empirical evidence, to develop a robust approach for the analysis and interpretation of data from longitudinal clinical trials. We propose that, in many settings, the primary efficacy analysis should use a repeated measures, likelihood-based, mixed-effects modeling approach, with LOCF used as a secondary, composite measure of efficacy, safety, and tolerability. We illustrate how repeated-measures analyses can be used to enhance decision-making, and we review the caveats that remain regarding the use of LOCF as a composite measure.

Analysis of Variance↗
PubMed2003

Statistical models for analyzing repeated quality measurements of horticultural products. Model evaluations and practical example.

In the field of postharvest quality assessment of horticultural products, research on the development of non-destructive quality sensors, replacing destructive and often time consuming sensors, has spurred in the last decennium offering the possibility of taking repeated quality measures on the same product. Repeated measures analysis is gaining importance during recent years and several software packages offer a broad class of routines. A dataset dealing with the postharvest quality evolution of different tomato cultivars serves as practical example for the comparison and discussion of four different statistical model types. Starting from an analysis at each time point and an ordinary least squares regression model as standard and widely used methods, this contribution aims at comparing these two methods to a repeated measures analysis and a longitudinal mixed model. It is shown that the flexibility of such a mixed model, both towards the repeated measures design of the experiments as towards the large product variability inherent to these horticultural products, is an important advantage over classical techniques. This research shows that different conclusions could be drawn depending on which technique is used due to the basic assumptions of each model and which are not always fulfilled. The results further demonstrate the flexibility of the mixed model concept. Using a mixed model for repeated measures, the different sources of variability, being inter-tomato variability, intra-tomato variability and measurement error were characterized being of great benefit to the researcher.

Computer Simulation↗
PubMed2003

Heterogeneity of symptom pattern, psychosocial factors, and pathophysiological mechanisms in severe functional dyspepsia.

BACKGROUND & AIMS: Categorization of functional dyspepsia into subgroups is based on expert opinion according to (dominant) symptoms or on underlying pathophysiological mechanisms. We used an evidence-based approach to the determination of subtypes of functional dyspepsia. METHODS: Consecutive functional dyspepsia patients were recruited from a tertiary referral center. The following were performed: (1) exploratory (EFA) and confirmatory factor analysis (CFA) of symptom patterns in a large group of patients with functional dyspepsia; (2) external validation of these factors by the determination of their association pattern with physio- and psychopathological mechanisms, and with health-related quality of life and sickness behavior; and (3) cluster analysis of their distribution in this population. RESULTS: Both EFA and CFA do not support the existence of functional dyspepsia as a homogeneous (unidimensional) condition. A 4-factor model is found to be valid, with differential distribution within the patient population according to cluster analysis. Factor 1 is characterized by nausea, vomiting, early satiety, and weight loss and factor 2 by postprandial fullness and bloating. Both factor 1 and 2 are associated with delayed emptying, but only factor 1 is associated with younger age, female sex, and sickness behavior. Factor 3 is characterized by pain symptoms and associated with gastric hypersensitivity and several psychosocial dimensions including medically unexplained symptoms and health-related quality of life dimensions. Factor 4, characterized by belching, is also associated with hypersensitivity, but is unrelated to psychosocial dimensions. CONCLUSIONS: In a tertiary care population, functional dyspepsia is a heterogeneous condition characterized by 4 major dimensions differentially associated with psychopathological and physiopathological mechanisms.

Abdominal Pain↗
PubMed2003

The use of score tests for inference on variance components.

Whenever inference for variance components is required, the choice between one-sided and two-sided tests is crucial. This choice is usually driven by whether or not negative variance components are permitted. For two-sided tests, classical inferential procedures can be followed, based on likelihood ratios, score statistics, or Wald statistics. For one-sided tests, however, one-sided test statistics need to be developed, and their null distribution derived. While this has received considerable attention in the context of the likelihood ratio test, there appears to be much confusion about the related problem for the score test. The aim of this paper is to illustrate that classical (two-sided) score test statistics, frequently advocated in practice, cannot be used in this context, but that well-chosen one-sided counterparts could be used instead. The relation with likelihood ratio tests will be established, and all results are illustrated in an analysis of continuous longitudinal data using linear mixed models.

Analysis of Variance↗
PubMed2003

A local influence approach applied to binary data from a psychiatric study.

Recently, a lot of concern has been raised about assumptions needed in order to fit statistical models to incomplete multivariate and longitudinal data. In response, research efforts are being devoted to the development of tools that assess the sensitivity of such models to often strong but always, at least in part, unverifiable assumptions. Many efforts have been devoted to longitudinal data, primarily in the selection model context, although some researchers have expressed interest in the pattern-mixture setting as well. A promising tool, proposed by Verbeke et al. (2001, Biometrics 57, 43-50), is based on local influence (Cook, 1986, Journal of the Royal Statistical Society, Series B 48, 133-169). These authors considered the Diggle and Kenward (1994, Applied Statistics 43, 49-93) model, which is based on a selection model, integrating a linear mixed model for continuous outcomes with logistic regression for dropout. In this article, we show that a similar idea can be developed for multivariate and longitudinal binary data, subject to nonmonotone missingness. We focus on the model proposed by Baker, Rosenberger, and DerSimonian (1992, Statistics in Medicine 11, 643-657). The original model is first extended to allow for (possibly continuous) covariates, whereafter a local influence strategy is developed to support the model-building process. The model is able to deal with nonmonotone missingness but has some limitations as well, stemming from the conditional nature of the model parameters. Some analytical insight is provided into the behavior of the local influence graphs.

Antidepressive Agents, Tricyclic↗
PubMed2003

Graphical exploration of gene expression data: a comparative study of three multivariate methods.

This article describes three multivariate projection methods and compares them for their ability to identify clusters of biological samples and genes using real-life data on gene expression levels of leukemia patients. It is shown that principal component analysis (PCA) has the disadvantage that the resulting principal factors are not very informative, while correspondence factor analysis (CFA) has difficulties interpreting distances between objects. Spectral map analysis (SMA) is introduced as an alternative approach to the analysis of microarray data. Weighted SMA outperforms PCA, and is at least as powerful as CFA, in finding clusters in the samples, as well as identifying genes related to these clusters. SMA addresses the problem of data analysis in microarray experiments in a more appropriate manner than CFA, and allows more flexible weighting to the genes and samples. Proper weighting is important, since it enables less reliable data to be down-weighted and more reliable information to be emphasized.

Biometry↗
PubMed2002

Multicollinearity in prognostic factor analyses using the EORTC QLQ-C30: identification and impact on model selection.

Clinical and quality of life (QL) variables from an EORTC clinical trial of first line chemotherapy in advanced breast cancer were used in a prognostic factor analysis of survival and response to chemotherapy. For response, different final multivariate models were obtained from forward and backward selection methods, suggesting a disconcerting instability. Quality of life was measured using the EORTC QLQ-C30 questionnaire completed by patients. Subscales on the questionnaire are known to be highly correlated, and therefore it was hypothesized that multicollinearity contributed to model instability. A correlation matrix indicated that global QL was highly correlated with 7 out of 11 variables. In a first attempt to explore multicollinearity, we used global QL as dependent variable in a regression model with other QL subscales as predictors. Afterwards, standard diagnostic tests for multicollinearity were performed. An exploratory principal components analysis and factor analysis of the QL subscales identified at most three important components and indicated that inclusion of global QL made minimal difference to the loadings on each component, suggesting that it is redundant in the model. In a second approach, we advocate a bootstrap technique to assess the stability of the models. Based on these analyses and since global QL exacerbates problems of multicollinearity, we therefore recommend that global QL be excluded from prognostic factor analyses using the QLQ-C30. The prognostic factor analysis was rerun without global QL in the model, and selected the same significant prognostic factors as before.

Antineoplastic Agents↗
PubMed2002

Prediction of survival and opportunistic infections in HIV-infected patients: a comparison of imputation methods of incomplete CD4 counts.

In evaluating the risk of mortality or development of opportunistic infections in HIV-infected patients, the number of CD4 lymphocyte cells per cubic millimetre of blood is widely recognized as one of the best available predictors of such future events. However, its usefulness is limited by the incompleteness and variability of such CD4 measurements during follow-up. Because of these limitations, analysis of such data requires the missing measurements to be 'filled in' or the patients without them to be excluded. We consider multiple imputation of CD4 values based partly on information from other health status measures such as haemoglobin, as well as on the event status of interest. These alternative health status measures are also considered as possible independent predictors of survival endpoints. Our work is motivated by a cohort of 1530 patients enrolled in two AIDS clinical trials. We compare our approach to other strategies such as basing evaluation of risk on baseline CD4, the last measured CD4 before an event, or a time-dependent covariate based on carrying the last CD4 value forward; we conclude with a strong recommendation for multiple imputation.

AIDS-Related Opportunistic Infections↗
PubMed2002

Selection models and pattern-mixture models to analyse longitudinal quality of life data subject to drop-out.

Longitudinally observed quality of life data with large amounts of drop-out are analysed. First we used the selection modelling framework, frequently used with incomplete studies. An alternative method consists of using pattern-mixture models. These are also straightforward to implement, but result in a different set of parameters for the measurement and drop-out mechanisms. Since selection models and pattern-mixture models are based upon different factorizations of the joint distribution of measurement and drop-out mechanisms, comparing both models concerning, for example, treatment effect, is a useful form of a sensitivity analysis.

Aged↗