Mixed-effect hybrid models for longitudinal data with nonignorable dropout

Summary .  Selection models and pattern-mixture models are often used to deal with nonignorable dropout in longitudinal studies. These two classes of models are based on different factorizations of the joint distribution of the outcome process and the dropout process. We consider a new class of models, called mixed-effect hybrid models (MEHMs), where the joint distribution of the outcome process and dropout process is factorized into the marginal distribution of random effects, the dropout process conditional on random effects, and the outcome process conditional on dropout patterns and random effects. MEHMs combine features of selection models and pattern-mixture models: they directly model the missingness process as in selection models, and enjoy the computational simplicity of pattern-mixture models. The MEHM provides a generalization of shared-parameter models (SPMs) by relaxing the conditional independence assumption between the measurement process and the dropout process given random effects. Because SPMs are nested within MEHMs, likelihood ratio tests can be constructed to evaluate the conditional independence assumption of SPMs. We use data from a pediatric AIDS clinical trial to illustrate the models.     

On Estimating the Relationship between Longitudinal Measurements and Time‐to‐Event Data Using a Simple Two‐Stage Procedure

Summary Ye, Lin, and Taylor (2008, Biometrics 64 , 1238–1246) proposed a joint model for longitudinal measurements and time‐to‐event data in which the longitudinal measurements are modeled with a semiparametric mixed model to allow for the complex patterns in longitudinal biomarker data. They proposed a two‐stage regression calibration approach that is simpler to implement than a joint modeling approach. In the first stage of their approach, the mixed model is fit without regard to the time‐to‐event data. In the second stage, the posterior expectation of an individual's random effects from the mixed‐model are included as covariates in a Cox model. Although Ye et al. (2008) acknowledged that their regression calibration approach may cause a bias due to the problem of informative dropout and measurement error, they argued that the bias is small relative to alternative methods. In this article, we show that this bias may be substantial. We show how to alleviate much of this bias with an alternative regression calibration approach that can be applied for both discrete and continuous time‐to‐event data. Through simulations, the proposed approach is shown to have substantially less bias than the regression calibration approach proposed by Ye et al. (2008) . In agreement with the methodology proposed by Ye et al. (2008) , an advantage of our proposed approach over joint modeling is that it can be implemented with standard statistical software and does not require complex estimation techniques.     

Tumor necrosis factor alpha gene variants do not display allelic imbalance in circulating myeloid cells

Carriage of the TNF −308 A allele (rs1800629 A) has been associated with increased serum TNF-α levels, the development of sepsis syndrome, and fatal outcome, in severely traumatized patients (Menges et al., 2008 [1]). Herein, we analysed the putative allelic imbalance of TNF-α release from myeloid cells. Circulating peripheral blood cells from healthy human blood donors (n = 104) and monocyte-derived macrophages (n = 158) were analysed for their ex vivo capacity of TNF-α expression. Our findings indicate that carriage of the TNF −308 A allele is not associated with high TNF-α expression in circulating human leucocytes and monocyte-derived macrophages. Other cellular sources, e.g. tissue-resident cells like mast cells and/or tissue specific macrophages might be the cellular source of high TNF-α serum levels shortly after trauma.     

A rapid and simple method for inactivating chromosomal genes in Yersinia

A polymerase chain reaction (PCR)-based procedure without any cloning step was developed for a rapid mutagenesis/deletion of chromosomal target genes in Yersinia. For this purpose, a PCR fragment carrying an antibiotic resistance gene flanked by regions homologous to the target locus is electroporated into a recipient strain expressing the highly proficient homologous recombination system encoded by plasmid pKOBEG-sacB. Two PCR procedures were tested to generate an amplification product formed of an antibiotic resistance gene flanked by short (55 bp) or long (500 bp) homology extensions. Using this method, three chromosomal loci were successfully disrupted in Yersinia pseudotuberculosis. The use of this technique allows rapid and efficient large-scale mutagenesis of Yersinia target chromosomal genes.     

Genetic approaches to study Legionella pneumophila pathogenicity

Abstract: Legionella pneumophila is an intracellular pathogen replicating in human macrophages during the course of infection of the lungs, infection by legionellae often leads to severe pneumonia, termed Legionnaires' disease. Genetic approaches to identify the factors responsible for L. pneumophila pathogenicity started with the construction of genomic libraries in Escherichia coli. Various L. pneumophila -specific genes were cloned in E. coli K-12 by identifaction using functional assays, antibody screening and hybridization ('reverse genetics'). By disrupting the genes via allelic exchange, mutants have been created to assess the influence of the factors on pathogenicity. Among the cloned genes, only for the gene product of the mip gene, encoding a 24-kDa surface-associated protein (macrophage infectivity potentiator) unequivocal evidence for its contribution to pathogenicity could be provided. Two hemolytic factors that have been cloned do not seem to play a role in L. pneumophila pathogenicity. Genetic systems for transposon mutagenesis of the L. pneumophila genome (Tn5, Tn903dlIlacZ, MudphoA), including TnphoA shuttle mutagenesis, have been established and specifically adapted to identify mutants which displayed an impaired capability to multiply inside macrophages and with a reduced in vivo virulence. Furthermore, by complementation of avirulent mutants, genetic loci could be identified which restored the virulence.     

Identification and genetic mapping of Xenopus TAP2 genes

 The amphibian Xenopus laevis is one non-mammalian vertebrate in which the major histocompatibility complex (MHC) has been analyzed extensively. Class IIβ, class Ia, LMP2, LMP7, HSP70, C4, Factor B, and Ring3 genes have been identified and mapped to the MHC. Here, we report the isolation of a transporter associated with antigen processing (TAP) gene, TAP2, and demonstrate its linkage to the MHC. While the ATP-binding region of Xenopus TAP2 is highly conserved in evolution, amino acid identity to other vertebrate TAP proteins was not detected in the N-terminal region. Segregation analysis of 34 individuals from two families showed exact restriction fragment length polymorphism matching between the MHC class Ia gene and the one TAP2 gene demonstrating linkage conservation since the mammalian/amphibian divergence ∼350 million years ago. In addition, one non-MHC-linked TAP2–hybridizing fragment was detected in approximately half of the individuals tested. Interestingly, TAP2 allelic lineages appear to match those of LMP7 and classical class I, which previously were categorized into two highly divergent groups that emerged at least 60 million years ago. Similar to LMP7 and class Ia,TAP2 is expressed ubiquitously with highest levels in intestine and spleen. Received: 2 March 1998 / Revised: 15 July 1998     

Population study of allelic diversity in the human MHC class I-related MIC-A gene

 The polymorphism of major histocompatibility complex (MHC) class I HLA-A, -B, and -C molecules may have evolved through pathogen-driven selection of alleles with diverse peptide-binding specificities. Two MHC-encoded molecules that are distantly related to class I, MIC-A and MIC-B, do not function in the presentation of pathogen-derived peptides to T cells with αβ T-cell receptors (TCRs), but are broadly recognized by intraepithelial T cells with γδ TCRs. However, both MIC-A and MIC-B are polymorphic, displaying an unusual distribution of a number of variant amino acids in their extracellular α1, α2, and α3 domains. In order to further define the polymorphism of MIC-A, we examined its alleles among 275 individuals with common and rare HLA genotypes. Of 16 previously defined alleles, 12 were confirmed and 5 new alleles were identified. A two-by-two analysis of MIC-A and HLA-B alleles uncovered a number of statistically significant associations. These results confirm and extend previous knowledge on the polymorphism of MIC-A. The strong positive linkage of certain MIC-A and HLA-B alleles may have implications for studies related to MHC-associated diseases and transplantation. Received: 5 August 1998 / Revised: 26 October 1998     

B lymphocytes--a dogma revisited

The one B cell-one antibody hypothesis proposed by M.F. Burnet (1957) was recently challenged by results showing that one B cell can simultaneously express an auto-reactive BCR, and a BCR directed against non-self antigens. The latter allows this auto-reactive B cell to escape negative selection. Burnet's theory was thus challenged from the beginning. Namely, Liacopoulos et al. demonstrated that normal B cells produce simultaneously or sequentially two antibody molecules against two unrelated haptens. It thus appears that 'double producers' provide new prospects in auto-immunity. Our previous work using heterologous antigens also suggest that 'double producers' provide an amplifying factor for immunoglobulin repertoire.