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Cambridge, United Kingdom

Asante E.A.,University College London | Smidak M.,University College London | Grimshaw A.,University College London | Houghton R.,University College London | And 15 more authors.

Mammalian prions, transmissible agents causing lethal neurodegenerative diseases, are composed of assemblies of misfolded cellular prion protein (PrP). A novel PrP variant, G127V, was under positive evolutionary selection during the epidemic of kuru - an acquired prion disease epidemic of the Fore population in Papua New Guinea - and appeared to provide strong protection against disease in the heterozygous state. Here we have investigated the protective role of this variant and its interaction with the common, worldwide M129V PrP polymorphism. V127 was seen exclusively on a M129 PRNP allele. We demonstrate that transgenic mice expressing both variant and wild-type human PrP are completely resistant to both kuru and classical Creutzfeldt-Jakob disease (CJD) prions (which are closely similar) but can be infected with variant CJD prions, a human prion strain resulting from exposure to bovine spongiform encephalopathy prions to which the Fore were not exposed. Notably, mice expressing only PrP V127 were completely resistant to all prion strains, demonstrating a different molecular mechanism to M129V, which provides its relative protection against classical CJD and kuru in the heterozygous state. Indeed, this single amino acid substitution (G-V) at a residue invariant in vertebrate evolution is as protective as deletion of the protein. Further study in transgenic mice expressing different ratios of variant and wild-type PrP indicates that not only is PrP V127 completely refractory to prion conversion but acts as a potent dose-dependent inhibitor of wild-type prion propagation. © 2015 Macmillan Publishers Limited. All rights reserved. Source

Walter F.M.,University of Cambridge | Prevost A.T.,Kings College London | Hall P.N.,University of Western Australia | Burrows N.P.,University of Cambridge | And 2 more authors.
British Journal of General Practice

Background GPs need to recognise significant pigmented skin lesions, given rising UK incidence rates for malignant melanoma. The 7-point checklist (7PCL) has been recommended by NICE (2005) for routine use in UK general practice to identify clinically significant lesions which require urgent referral. Aim To validate the Original and Weighted versions of the 7PCL in the primary care setting. Design and setting Diagnostic validation study, using data from a SIAscopic diagnostic aid randomised controlled trial in eastern England. Method Adults presenting in general practice with a pigmented skin lesion that could not be immediately diagnosed as benign were recruited into the trial. Reference standard diagnoses were histology or dermatology expert opinion; 7PCL scores were calculated blinded to the reference diagnosis. A case was defined as a clinically significant lesion for primary care referral to secondary care (total 1436 lesions: 225 cases, 1211 controls); or melanoma (36). Results For diagnosing clinically significant lesions there was a difference between the performance of the Original and Weighted 7PCLs (respectively, area under curve: 0.66, 0.69, difference = 0.03, P<0.001). For the identification of melanoma, similar differences were found. Increasing the Weighted 7PCL's cut-off score from recommended 3 to 4 improved detection of clinically significant lesions in primary care: sensitivity 73.3%, specificity 57.1%, positive predictive value 24.1%, negative predictive value 92.0%, while maintaining high sensitivity of 91.7% and moderate specificity of 53.4% for melanoma. Conclusion The Original and Weighted 7PCLs both performed well in a primary care setting to identify clinically significant lesions as well as melanoma. The Weighted 7PCL, with a revised cut-off score of 4 from 3, performs slightly better and could be applied in general practice to support the recognition of clinically significant lesions and therefore the early identification of melanoma. © British Journal of General Practice. Source

An adjustment for an uncorrelated covariate in a logistic regression changes the true value of an odds ratio for a unit increase in a risk factor. Even when there is no variation due to covariates, the odds ratio for a unit increase in a risk factor also depends on the distribution of the risk factor. We can use an instrumental variable to consistently estimate a causal effect in the presence of arbitrary confounding. With a logistic outcome model, we show that the simple ratio or two-stage instrumental variable estimate is consistent for the odds ratio of an increase in the population distribution of the risk factor equal to the change due to a unit increase in the instrument divided by the average change in the risk factor due to the increase in the instrument. This odds ratio is conditional within the strata of the instrumental variable, but marginal across all other covariates, and is averaged across the population distribution of the risk factor. Where the proportion of variance in the risk factor explained by the instrument is small, this is similar to the odds ratio from a RCT without adjustment for any covariates, where the intervention corresponds to the effect of a change in the population distribution of the risk factor. This implies that the ratio or two-stage instrumental variable method is not biased, as has been suggested, but estimates a different quantity to the conditional odds ratio from an adjusted multiple regression, a quantity that has arguably more relevance to an epidemiologist or a policy maker, especially in the context of Mendelian randomization. © 2013 John Wiley & Sons, Ltd. Source

Morris T.P.,Hub for Trials Methodology Research | Morris T.P.,Institute of Public Health | White I.R.,Institute of Public Health | Royston P.,Hub for Trials Methodology Research | And 2 more authors.
Statistics in Medicine

We are concerned with multiple imputation of the ratio of two variables, which is to be used as a covariate in a regression analysis. If the numerator and denominator are not missing simultaneously, it seems sensible to make use of the observed variable in the imputation model. One such strategy is to impute missing values for the numerator and denominator, or the log-transformed numerator and denominator, and then calculate the ratio of interest; we call this 'passive' imputation. Alternatively, missing ratio values might be imputed directly, with or without the numerator and/or the denominator in the imputation model; we call this 'active' imputation. In two motivating datasets, one involving body mass index as a covariate and the other involving the ratio of total to high-density lipoprotein cholesterol, we assess the sensitivity of results to the choice of imputation model and, as an alternative, explore fully Bayesian joint models for the outcome and incomplete ratio. Fully Bayesian approaches using Winbugs were unusable in both datasets because of computational problems. In our first dataset, multiple imputation results are similar regardless of the imputation model; in the second, results are sensitive to the choice of imputation model. Sensitivity depends strongly on the coefficient of variation of the ratio's denominator. A simulation study demonstrates that passive imputation without transformation is risky because it can lead to downward bias when the coefficient of variation of the ratio's denominator is larger than about 0.1. Active imputation or passive imputation after log-transformation is preferable. © 2013 The Authors. Statistics in Medicine published by John Wiley & Sons, Ltd.. Source

Yates M.,Norwich University | Cheong E.,Norwich University | Luben R.,Strangeways Research Laboratory | Igali L.,Norwich University | And 4 more authors.
Digestive Diseases and Sciences

Background: The timing of the risk factors cigarette smoking, alcohol and obesity in the development of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) is unclear. Aims: To investigate these exposures in the aetiology of BE and EAC in the same population. Methods: The cohort included 24,068 men and women, aged 39-79 years, recruited between 1993 and 1997 into the prospective EPIC-Norfolk Study who provided information on anthropometry, smoking and alcohol intake. The cohort was monitored until December 2008 and incident cases identified. Results: One hundred and four participants were diagnosed with BE and 66 with EAC. A body mass index (BMI) above 23 kg/m 2 was associated with a greater risk of BE [BMI ≥23 vs. 18.5 to <23, hazard ratio (HR) 3.73, 95 % CI 1.37-10.16], and within a normal BMI, the risk was greater in the higher category (HR 3.76, 95 % CI 1.30-10.85, BMI 23-25 vs. 18.5 to >23 kg/m2). Neither smoking nor alcohol intake were associated with risk for BE. For EAC, all BMI categories were associated with risk, although statistically significant for only the highest (BMI >35 vs. BMI 18.5 to <23, HR 4.95, 95 % CI 1.11-22.17). The risk was greater in the higher category of a normal BMI (HR 2.73, 95 % CI 0.93-8.00, p = 0.07, BMI 23-25 vs. 18.5 to >23 kg/m2). There was an inverse association with ≥7 units alcohol/week (HR 0.51, 95 % CI 0.29-0.88) and with wine (HR 0.49, 95 % CI 0.23-1.04, p = 0.06, drinkers vs. non-drinkers). Conclusions: Obesity may be involved early in carcinogenesis and the association with EAC and wine should be explored. The data have implications for aetiological investigations and prevention strategies. © 2014 The Author(s). Source

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