Computation of the asymptotic null distribution of goodness-of-fit tests for multi-state models.

We develop an improved approximation to the asymptotic null distribution of the goodness-of-fit tests for panel observed multi-state Markov models (Aguirre-Hernandez and Farewell, Stat Med 21:1899-1911, 2002) and hidden Markov models (Titman and Sharples, Stat Med 27:2177-2195, 2008). By considering the joint distribution of the grouped observed transition counts and the maximum likelihood estimate of the parameter vector it is shown that the distribution can be expressed as a weighted sum of independent X^2_1 random variables, where the weights are dependent on the true parameters. The performance of this approximation for finite sample sizes and where the weights are calculated using the maximum likelihood estimates of the parameters is considered through simulation. In the scenarios considered, the approximation performs well and is a substantial improvement over the simple X^2_1 approximation

EGFR gene variants are associated with specific somatic aberrations in glioma

A number of gene variants have been associated with an increased risk of developing glioma. We hypothesized that the reported risk variants may be associated with tumor genomic instability. To explore potential correlations between germline risk variants and somatic genetic events, we analyzed matched tumor and blood samples from 95 glioma patients by means of SNP genotyping. The generated genotype data was used to calculate genome-wide allele-specific copy number profiles of the tumor samples. We compared the copy number profiles across samples and found two EGFR gene variants (rs17172430 and rs11979158) that were associated with homozygous deletion at the CDKN2A/B locus. One of the EGFR variants (rs17172430) was also associated with loss of heterozygosity at the EGFR locus. Our findings were confirmed in a separate dataset consisting of matched blood and tumor samples from 300 glioblastoma patients, compiled from publically available TCGA data. These results imply there is a functional effect of germline EGFR variants on tumor progression

DNA-repair gene variants are associated with glioblastoma survival

Patient outcome from glioma may be influenced by germline variation. Considering the importance of DNA repair in cancer biology as well as in response to treatment, we studied the relationship between 1458 SNPs, which captured the majority of the common genetic variation in 136 DNA repair genes, in 138 glioblastoma samples from Sweden and Denmark. We confirmed our findings in an independent cohort of 121 glioblastoma patients from the UK. Our analysis revealed nine SNPs annotating MSH2, RAD51L1 and RECQL4 that were significantly (p < 0.05) associated with glioblastoma survival