6 research outputs found

    Model Selection Approach Suggests Causal Association between 25-Hydroxyvitamin D and Colorectal Cancer

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    Vitamin D deficiency has been associated with increased risk of colorectal cancer (CRC), but causal relationship has not yet been confirmed. We investigate the direction of causation between vitamin D and CRC by extending the conventional approaches to allow pleiotropic relationships and by explicitly modelling unmeasured confounders.Plasma 25-hydroxyvitamin D (25-OHD), genetic variants associated with 25-OHD and CRC, and other relevant information was available for 2645 individuals (1057 CRC cases and 1588 controls) and included in the model. We investigate whether 25-OHD is likely to be causally associated with CRC, or vice versa, by selecting the best modelling hypothesis according to Bayesian predictive scores. We examine consistency for a range of prior assumptions.Model comparison showed preference for the causal association between low 25-OHD and CRC over the reverse causal hypothesis. This was confirmed for posterior mean deviances obtained for both models (11.5 natural log units in favour of the causal model), and also for deviance information criteria (DIC) computed for a range of prior distributions. Overall, models ignoring hidden confounding or pleiotropy had significantly poorer DIC scores.Results suggest causal association between 25-OHD and colorectal cancer, and support the need for randomised clinical trials for further confirmations

    Echocardiographic/ Doppler criteria of normality, the findings in cardiac disease and the genetics of familial dilated cardiomyopathy in Newfoundland dogs

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    Dilated cardiomyopathy (DCM) is common in pedigree dog breeds including Newfoundlands. The breed predisposition and the familial prevalence within breeds support a genetic basis to the disease. Familial occurrence of DCM has only recently been recognised in man, and echocardiography abnormalities are common in relatives of DCM patients.Echocardiography is the method of choice for confirming the diagnosis of DCM. Echocardiographic/Doppler data are presented from 223 scans from 165 individual Newfoundland dogs. The scans were categorised into six groups based on the clinical presentation, M-mode echocardiography results and the Doppler derived aortic velocity. The Normal group showed no abnormalities (n=86). The DCM (overt or occult) group had a rounded left ventricle and fractional shortening (FS) <22% (n=35). There were two depressed fractional shortening groups, without other abnormalities; one with FS less than 18% (dFS<18%) (n=29) and the other with FS 18-20% (dFS18-20%) (n=24). The left ventricular enlargement (LVE) group was defined as a LV diastolic dimension greater than 55mm (males) or >50 mm (females), without any M-mode evidence of systolic dysfunction (n=8). Dogs with an aortic velocity exceeding 1.7 m/s were defined as showing evidence of subaortic stenosis (SAS group) (n=40).Data from complete echocardiographic/Doppler analysis of the Normal group were assessed for dependence on the gender, age and size of dog (weight or body surface area (BSA)) and the heart rate (mean R-R interval) by linear regression analyses. LV volumes and M-mode measurements were positively correlated with size. Gender was not an important predictor of most echo measurements once data was normalised for BSA. Advancing age was a significant negative predictor of LV volumes and dimensions although influence on wall thickness was not significant. Age also showed a significant influence on diastolic function, assessed by mitral inflow and pulmonary venous flow, similar to changes described in man.The Newfoundland groups were compared. The DCM group had significantly increased LV volume and dimensions and decreased systolic function than other groups. There were few significant differences between the groups for diastolic function parameters. There was considerable overlap between groups for all dimensions and the parameters of systolic function, although the pre-ejection period: ejection time (PEP:ET) ratio appeared to be most sensitive for distinguishing normal from DCM dogs. In both dFS groups and the LVE group, this ratio was intermediate between the Normal and DCM groups, in contrast to other parameters of systolic function. Left atrial dysfunction was also identified in the DCM group, but was less marked in both dFS and the LVE groups. Some dogs in the LVE and dFS groups progressed to develop DCM but a longer duration of study would be required before firm conclusions can be drawn about progression.Most of the dogs in this study were related. Pedigree and segregation analyses were supportive but not conclusive for an autosomal dominant mode of inheritance for DCM. A simulated linkage analysis indicated that this family was sufficiently informative for a genetic linkage analysis study. A pilot study assessing a number of anonymous canine microsatellites confirmed that there was sufficient heterozygosity and polymorphism, despite significant inbreeding, to permit a genetic linkage analysis study. No significant LOD score was achieved for the twelve microsatellites assessed. However, the available data indicate that a genome-wide linkage analysis is likely to be successful, with phenotyping based on the echocardiography data
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