Relations Between Measures of Irritability and Contingency Detection at 6 Months

The hypothesis that irritability and contingency detection are negatively correlated was examined in thirty‐one 6‐month‐old infants. Observation and maternal report‐based assessments of irritability were correlated with both a criterion score and a continuous score of contingency detection. Results indicated that greater irritability in infants was associated with lower contingency detection scores. Discussion focuses on identifying processes by which the 2 constructs may be associated.     

Type I error rates from likelihood‐based repeated measures analyses of incomplete longitudinal data

The last observation carried forward (LOCF) approach is commonly utilized to handle missing values in the primary analysis of clinical trials. However, recent evidence suggests that likelihood‐based analyses developed under the missing at random (MAR) framework are sensible alternatives. The objective of this study was to assess the Type I error rates from a likelihood‐based MAR approach – mixed‐model repeated measures (MMRM) – compared with LOCF when estimating treatment contrasts for mean change from baseline to endpoint (Δ). Data emulating neuropsychiatric clinical trials were simulated in a 4 × 4 factorial arrangement of scenarios, using four patterns of mean changes over time and four strategies for deleting data to generate subject dropout via an MAR mechanism. In data with no dropout, estimates of Δ and SE_Δ from MMRM and LOCF were identical. In data with dropout, the Type I error rates (averaged across all scenarios) for MMRM and LOCF were 5.49% and 16.76%, respectively. In 11 of the 16 scenarios, the Type I error rate from MMRM was at least 1.00% closer to the expected rate of 5.00% than the corresponding rate from LOCF. In no scenario did LOCF yield a Type I error rate that was at least 1.00% closer to the expected rate than the corresponding rate from MMRM. The average estimate of SE_Δ from MMRM was greater in data with dropout than in complete data, whereas the average estimate of SE_Δ from LOCF was smaller in data with dropout than in complete data, suggesting that standard errors from MMRM better reflected the uncertainty in the data. The results from this investigation support those from previous studies, which found that MMRM provided reasonable control of Type I error even in the presence of MNAR missingness. No universally best approach to analysis of longitudinal data exists. However, likelihood‐based MAR approaches have been shown to perform well in a variety of situations and are a sensible alternative to the LOCF approach. MNAR methods can be used within a sensitivity analysis framework to test the potential presence and impact of MNAR data, thereby assessing robustness of results from an MAR method. Copyright © 2004 John Wiley & Sons, Ltd.     

Choice of the primary analysis in longitudinal clinical trials

Missing data, and the bias they can cause, are an almost ever‐present concern in clinical trials. The last observation carried forward (LOCF) approach has been frequently utilized to handle missing data in clinical trials, and is often specified in conjunction with analysis of variance (LOCF ANOVA) for the primary analysis. Considerable advances in statistical methodology, and in our ability to implement these methods, have been made in recent years. Likelihood‐based, mixed‐effects model approaches implemented under the missing at random (MAR) framework are now easy to implement, and are commonly used to analyse clinical trial data. Furthermore, such approaches are more robust to the biases from missing data, and provide better control of Type I and Type II errors than LOCF ANOVA. Empirical research and analytic proof have demonstrated that the behaviour of LOCF is uncertain, and in many situations it has not been conservative. Using LOCF as a composite measure of safety, tolerability and efficacy can lead to erroneous conclusions regarding the effectiveness of a drug. This approach also violates the fundamental basis of statistics as it involves testing an outcome that is not a physical parameter of the population, but rather a quantity that can be influenced by investigator behaviour, trial design, etc. Practice should shift away from using LOCF ANOVA as the primary analysis and focus on likelihood‐based, mixed‐effects model approaches developed under the MAR framework, with missing not at random methods used to assess robustness of the primary analysis. Copyright © 2004 John Wiley & Sons, Ltd.     

Phonological Specificity in 12‐ and 17‐Month‐Old French‐Speaking Infants

The literature reports some contradictory results on the degree of phonological specificity of infants’ early lexical representations in the Romance language, French, and Germanic languages. It is not clear whether these discrepancies are because of differences in method, in language characteristics, or in participants’ age. In this study, we examined whether 12‐ and 17‐month‐old French‐speaking infants are able to distinguish well‐pronounced from mispronounced words (one or two features of their initial consonant). To this end, 46 infants participated in a preferential looking experiment in which they were presented with pairs of pictures together with a spoken word well pronounced or mispronounced. The results show that both 12‐ and 17‐month‐old infants look longer at the pictures corresponding to well‐pronounced words than to mispronounced words, but show no difference between the two mispronunciation types. These results suggest that, as early as 12 months, French‐speaking infants, like those exposed to Germanic languages, already possess detailed phonological representations of familiar words.     

Integrated nested Laplace approximation for the analysis of count data via the combined model: A simulation study

The combined model accounts for different forms of extra-variability and has traditionally been applied in the likelihood framework, or in the Bayesian setting via Markov chain Monte Carlo. In this article, integrated nested Laplace approximation is investigated as an alternative estimation method for the combined model for count data, and compared with the former estimation techniques. Longitudinal, spatial, and multi-hierarchical data scenarios are investigated in three case studies as well as a simulation study. As a conclusion, integrated nested Laplace approximation provides fast and precise estimation, while avoiding convergence problems often seen when using Markov chain Monte Carlo.     

Local influence diagnostics for generalized linear mixed models with overdispersion

Since the seminal paper by Cook and Weisberg [9 R.D. Cook and S. Weisberg, Residuals and Influence in Regression, Chapman &; Hall, London, 1982. [Google Scholar]], local influence, next to case deletion, has gained popularity as a tool to detect influential subjects and measurements for a variety of statistical models. For the linear mixed model the approach leads to easily interpretable and computationally convenient expressions, not only highlighting influential subjects, but also which aspect of their profile leads to undue influence on the model's fit [17 E. Lesaffre and G. Verbeke, Local influence in linear mixed models, Biometrics 54 (1998), pp. 570–582. doi: 10.2307/3109764[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]]. Ouwens et al. [24 M.J.N.M. Ouwens, F.E.S. Tan, and M.P.F. Berger, Local influence to detect influential data structures for generalized linear mixed models, Biometrics 57 (2001), pp. 1166–1172. doi: 10.1111/j.0006-341X.2001.01166.x[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]] applied the method to the Poisson-normal generalized linear mixed model (GLMM). Given the model's nonlinear structure, these authors did not derive interpretable components but rather focused on a graphical depiction of influence. In this paper, we consider GLMMs for binary, count, and time-to-event data, with the additional feature of accommodating overdispersion whenever necessary. For each situation, three approaches are considered, based on: (1) purely numerical derivations; (2) using a closed-form expression of the marginal likelihood function; and (3) using an integral representation of this likelihood. Unlike when case deletion is used, this leads to interpretable components, allowing not only to identify influential subjects, but also to study the cause thereof. The methodology is illustrated in case studies that range over the three data types mentioned.     

A pattern-mixture odds ratio model for incomplete categorical data

Most models for incomplete data are formulated within the selection model framework. Pattern-mixture models are increasingly seen as a viable alternative, both from an interpretational as well as from a computational point of view (Little 1993, Hogan and Laird 1997, Ekholm and Skinner 1998). Whereas most applications are either for continuous normally distributed data or for simplified categorical settings such as contingency tables, we show how a multivariate odds ratio model (Molenberghs and Lesaffre 1994, 1998) can be used to fit pattern-mixture models to repeated binary outcomes with continuous covariates. Apart from point estimation, useful methods for interval estimation are presented and data from a clinical study are analyzed to illustrate the methods.     

Quantile Regression Methods for Longitudinal Data with Drop-outs: Application to CD4 Cell Counts of Patients Infected with the Human Immunodeficiency Virus

Patients infected with the human immunodeficiency virus (HIV) generally experience a decline in their CD4 cell count (a count of certain white blood cells). We describe the use of quantile regression methods to analyse longitudinal data on CD4 cell counts from 1300 patients who participated in clinical trials that compared two therapeutic treatments: zidovudine and didanosine. It is of scientific interest to determine any treatment differences in the CD4 cell counts over a short treatment period. However, the analysis of the CD4 data is complicated by drop-outs: patients with lower CD4 cell counts at the base-line appear more likely to drop out at later measurement occasions. Motivated by this example, we describe the use of `weighted' estimating equations in quantile regression models for longitudinal data with drop-outs. In particular, the conventional estimating equations for the quantile regression parameters are weighted inversely proportionally to the probability of drop-out. This approach requires the process generating the missing data to be estimable but makes no assumptions about the distribution of the responses other than those imposed by the quantile regression model. This method yields consistent estimates of the quantile regression parameters provided that the model for drop-out has been correctly specified. The methodology proposed is applied to the CD4 cell count data and the results are compared with those obtained from an `unweighted' analysis. These results demonstrate how an analysis that fails to account for drop-outs can mislead.