Analysing mark-recapture-recovery data in the presence of missing covariate data via multiple imputation

We consider mark–recapture–recovery data with additional individual time-varying continuous covariate data. For such data it is common to specify the model parameters, and in particular the survival probabilities, as a function of these covariates to incorporate individual heterogeneity. However, an issue arises in relation to missing covariate values, for (at least) the times when an individual is not observed, leading to an analytically intractable likelihood. We propose a two-step multiple imputation approach to obtain estimates of the demographic parameters. Firstly, a model is fitted to only the observed covariate values. Conditional on the fitted covariate model, multiple “complete” datasets are generated (i.e. all missing covariate values are imputed). Secondly, for each complete dataset, a closed form complete data likelihood can be maximised to obtain estimates of the model parameters which are subsequently combined to obtain an overall estimate of the parameters. Associated standard errors and 95 % confidence intervals are obtained using a non-parametric bootstrap. A simulation study is undertaken to assess the performance of the proposed two-step approach. We apply the method to data collected on a well-studied population of Soay sheep and compare the results with a Bayesian data augmentation approach. Supplementary materials accompanying this paper appear on-line.Publisher PDFPeer reviewe

Characterisation of the genomic architecture of human chromosome 17q and evaluation of different methods for haplotype block definition

BACKGROUND: The selection of markers in association studies can be informed through the use of haplotype blocks. Recent reports have determined the genomic architecture of chromosomal segments through different haplotype block definitions based on linkage disequilibrium (LD) measures or haplotype diversity criteria. The relative applicability of distinct block definitions to association studies, however, remains unclear. We compared different block definitions in 6.1 Mb of chromosome 17q in 189 unrelated healthy individuals. Using 137 single nucleotide polymorphisms (SNPs), at a median spacing of 15.5 kb, we constructed haplotype block maps using published methods and additional methods we have developed. Haplotype tagging SNPs (htSNPs) were identified for each map. RESULTS: Blocks were found to be shorter and coverage of the region limited with methods based on LD measures, compared to the method based on haplotype diversity. Although the distribution of blocks was highly variable, the number of SNPs that needed to be typed in order to capture the maximum number of haplotypes was consistent. CONCLUSION: For the marker spacing used in this study, choice of block definition is not important when used as an initial screen of the region to identify htSNPs. However, choice of block definition has consequences for the downstream interpretation of association study results

Association of the FCRL3 gene with rheumatoid arthritis: a further example of population specificity?

Association of a functional promoter polymorphism mapping to the Fc receptor-like 3 (FCRL3) gene has recently been reported and replicated with rheumatoid arthritis (RA) in Japanese populations. The aim of this study was to investigate association of the FCRL3 gene with RA in UK subjects. DNA was available from 1065 patients with RA and 2073 population controls from the UK. Four single nucleotide polymorphism (SNP) markers (FCRL3-169*C/T (fclr3_3, rs7528684), fclr3_4 (rs11264799), fclr3_5 (rs945635), fclr3_6 (rs3761959)) all previously associated with RA in a Japanese population were genotyped in 761 RA samples and 484 controls. In the remaining samples, only the putative disease causal polymorphism, FCRL3-169*C/T, was tested. Genotyping was performed using either the Sequenom MassArray iPlex platform or a 5' Allelic discrimination assay (Taqman, ABI). Extensive linkage disequilibrium was present across the promoter SNPs genotyped (r(2) values = 0.60-0.98). Allele frequencies did not differ between RA cases and controls either for the putative disease causal polymorphism (odds ratio FCRL3-169*C allele = 0.97 (0.87-1.07), p = 0.51) or for the other SNPs tested. Similarly, no association was detected with RA using haplotype analysis or when stratification by shared epitope carriage or by presence of rheumatoid factor was undertaken. This study was powered to detect an effect size of 1.24 or greater for the FCRL3-169*C/T functional promoter polymorphism but no evidence for association was detected, suggesting that this gene will not have a substantial effect in determining susceptibility to RA in populations of Northern European descent

Oral splints for patients with temporomandibular disorders or bruxism : a systematic review and economic evaluation

This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 7. See the NIHR Journals Library website for further project information.Peer reviewedPublisher PD

Oral splints for temporomandibular disorder or bruxism : a systematic review

Funded by: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment Programme (Project number: 16/146/06). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.Peer reviewedPublisher PD

Identifying Causal Genes at the Multiple Sclerosis Associated Region 6q23 Using Capture Hi-C.

BACKGROUND: The chromosomal region 6q23 has been found to be associated with multiple sclerosis (MS) predisposition through genome wide association studies (GWAS). There are four independent single nucleotide polymorphisms (SNPs) associated with MS in this region, which spans around 2.5 Mb. Most GWAS variants associated with complex traits, including these four MS associated SNPs, are non-coding and their function is currently unknown. However, GWAS variants have been found to be enriched in enhancers and there is evidence that they may be involved in transcriptional regulation of their distant target genes through long range chromatin looping. AIM: The aim of this work is to identify causal disease genes in the 6q23 locus by studying long range chromatin interactions, using the recently developed Capture Hi-C method in human T and B-cell lines. Interactions involving four independent associations unique to MS, tagged by rs11154801, rs17066096, rs7769192 and rs67297943 were analysed using Capture Hi-C Analysis of Genomic Organisation (CHiCAGO). RESULTS: We found that the pattern of chromatin looping interactions in the MS 6q23 associated region is complex. Interactions cluster in two regions, the first involving the rs11154801 region and a second containing the rs17066096, rs7769192 and rs67297943 SNPs. Firstly, SNPs located within the AHI1 gene, tagged by rs11154801, are correlated with expression of AHI1 and interact with its promoter. These SNPs also interact with other potential candidate genes such as SGK1 and BCLAF1. Secondly, the rs17066096, rs7769192 and rs67297943 SNPs interact with each other and with immune-related genes such as IL20RA, IL22RA2, IFNGR1 and TNFAIP3. Finally, the above-mentioned regions interact with each other and therefore, may co-regulate these target genes. CONCLUSION: These results suggest that the four 6q23 variants, independently associated with MS, are involved in the regulation of several genes, including immune genes. These findings could help understand mechanisms of disease and suggest potential novel therapeutic targets