The dystrophin gene and cognitive function in the general population

The aim of our study is to investigate whether single-nucleotide dystrophin gene (DMD) variants associate with variability in cognitive functions in healthy populations. The study included 1240 participants from the Erasmus Rucphen family (ERF) study and 1464 individuals from the Rotterdam Study (RS). The participants whose exomes were sequenced and who were assessed for various cognitive traits were included in the analysis. To determine the association between DMD variants and cognitive ability, linear (mixed) modeling with adjustment for age, sex and education was used. Moreover, Sequence Kernel Association Test (SKAT) was used to test the overall association of the rare genetic variants present in the DMD with cognitive traits. Although no DMD variant surpassed the prespecified significance threshold (P<1 × 10⁻⁴), rs147546024:A>G showed strong association (β=1.786, P-value=2.56 × 10⁻⁴) with block-design test in the ERF study, while another variant rs1800273:G>A showed suggestive association (β=−0.465, P-value=0.002) with Mini-Mental State Examination test in the RS. Both variants are highly conserved, although rs147546024:A>G is an intronic variant, whereas rs1800273:G>A is a missense variant in the DMD which has a predicted damaging effect on the protein. Further gene-based analysis of DMD revealed suggestive association (P-values=0.087 and 0.074) with general cognitive ability in both cohorts. In conclusion, both single variant and gene-based analyses suggest the existence of variants in the DMD which may affect cognitive functioning in the general populations.     

Flexible selection of a single treatment incorporating short‐term endpoint information in a phase II/III clinical trial

Seamless phase II/III clinical trials in which an experimental treatment is selected at an interim analysis have been the focus of much recent research interest. Many of the methods proposed are based on the group sequential approach. This paper considers designs of this type in which the treatment selection can be based on short‐term endpoint information for more patients than have primary endpoint data available. We show that in such a case, the familywise type I error rate may be inflated if previously proposed group sequential methods are used and the treatment selection rule is not specified in advance. A method is proposed to avoid this inflation by considering the treatment selection that maximises the conditional error given the data available at the interim analysis. A simulation study is reported that illustrates the type I error rate inflation and compares the power of the new approach with two other methods: a combination testing approach and a group sequential method that does not use the short‐term endpoint data, both of which also strongly control the type I error rate. The new method is also illustrated through application to a study in Alzheimer's disease. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.     

Increased CD4+ T cell infiltrates in rheumatoid arthritis-associated interstitial pneumonitis compared with idiopathic interstitial pneumonitis

OBJECTIVE: To study lymphocyte markers in rheumatoid arthritis (RA)-associated interstitial pneumonitis (IP) compared with idiopathic IP. METHODS: Paraffin-embedded lung biopsy specimens from patients with RA (n = 15) and from those without RA (n = 16), all of whom had a diagnosis of either nonspecific IP or usual IP, were studied. Tissue sections from each patient were reviewed by a pathologist, who was blinded to the clinical data. Age and pulmonary function test results were similar in RA and non-RA patients. After high-temperature antigen unmasking, sections were incubated with mouse monoclonal antibodies directed against CD3, CD4, CD8, CD16, and CD20. All slides were coded, and digital images (100x magnification) of the entire tissue area were obtained. Staining was quantified using computer-assisted image analysis. RESULTS: Staining for CD4 was more prominent in patients with RA than in the non-RA comparison group (median 9.3 cells/mm(2), interquartile range [IQR] 5.5-27.3 versus 0.6 cells/mm(2), IQR 0.2-1.9; P = 0.002). CD4+ cell counts were increased in RA patients with nonspecific IP as well as in RA patients with usual IP, with no major difference between these groups. Results were similar for quantification of CD3 (P = 0.012). There was a less striking trend toward more CD8+ cells in RA patients (P = 0.27 versus those with non-RA lung disease). CONCLUSION: IP lesions in patients with RA are characterized by an increased number of CD4+ cells, as compared with that in patients with idiopathic IP. This finding suggests that CD4+ T cells are critical for the development of pulmonary manifestations in RA, and may have implications for the treatment of RA-associated lung disease.