Atrial fibrillation (AF) carries an increased risk of ischaemic stroke, and oral anticoagulation with warfarin can reduce this risk. The objective of this study was to evaluate the association between time in therapeutic International Normalised Ratio (INR) range when receiving warfarin and the risk of stroke and mortality. The study cohort included AF patients aged 40 years and older included in the UK General Practice Research Database. For patients treated with warfarin we computed the percentage of follow-up time spent within therapeutic range. Cox regression was used to assess the association between INR and outcomes while controlling for patient demographics, health status and concomitant medication. The study population included 27,458 warfarin-treated (with at least 3 INR measurements) and 10,449 patients not treated with antithrombotic therapy. Overall the warfarin users spent 63% of their time within therapeutic range (TTR). This percentage did not vary substantially by age, sex and CHA2DS2-VASc score. Patients who spent at least 70% of time within therapeutic range had a 79% reduced risk of stroke compared to patients with ≤30% of time in range (adjusted relative rate of 0.21; 95% confidence interval 0.18-0.25). Mortality rates were also significantly lower with at least 70% of time spent within therapeutic range. In conclusion, good anticoagulation control was associated with a reduction in the risk of stroke.

Current published risk schemes have modest predictive value for stroke. A new scheme (CHA(2) DS(2) -VASc) may discriminate those at truly low risk and minimize classification of subjects as intermediate/moderate risk. This approach would simplify our approach to stroke risk stratification and improve decision-making for thromboprophylaxis in patients with AF.

We conduct an extensive simulation study to compare the merits of several methods for using null (unlinked) markers to protect against false positives due to cryptic substructure in population-based genetic association studies. The more sophisticated "structured association" methods perform well but are computationally demanding and rely on estimating the correct number of subpopulations. The simple and fast "genomic control" approach can lose power in certain scenarios. We find that procedures based on logistic regression that are flexible, computationally fast, and easy to implement also provide good protection against the effects of cryptic substructure, even though they do not explicitly model the population structure.Population-based association studies provide an attractive approach to the identification of susceptibility genes underlying complex genetic traits. However, the recent track record of such studies has been mixed: Many reported associations have not been replicated, and the number of confirmed, positive associations to date is less than might have been expected a few years ago. Some of the nonreplicated reported associations might be due to population structure. If a higher proportion of cases than controls is sampled from a particular subpopulation, for example, because of biased ascertainment or higher prevalence of the disease in that subpopulation, then association can potentially be detected between case-control status and any markers having unusual allele frequencies in that subpopulation. Many such associations will be spurious: not due to any causal relationship between phenotype and genomic variants in the vicinity of the marker. If the population structure is recognized, it can be accounted for either at the design or the analysis stage of a study. Thus, the most important potential threat from population structure arises when the structure is unknown, so-called cryptic substructure. Freedman et al. (2004) observed that even well-designed studies can incorporate modest levels of cryptic substructure, enough to generate a substantial risk of false positives. Similarly Helgason et al. (2005) detected population structure within Iceland, which would normally be regarded as genetically homogeneous for the purposes of study design. Differentiation among the Icelandic regions is modest, with F ST estimates well below 1%, and is most pronounced in older individuals, but it is sufficient to generate a noticeable inflation of the type 1 error rate for genetic association studies. Recently Campbell et al. (2005) reported an SNP associated with height in European Americans, but they argued that the association was due to population substructure.Since the mid-1990s, many researchers have protected themselves against spurious associations due to cryptic substructure by implementing family-based designs (Thomson 1995) that eliminate the problem, for example, by matching spouses. Family-based studies remain widely used, and are being further developed (Van Steen et al. 2005). However, family-based d...

ObjectivesWe used national data to study differences in academic achievement between 5-year-old children with an isolated oral cleft and the general population. We also assessed differences by cleft type.MethodsChildren born in England with an oral cleft were identified in a national cleft registry. Their records were linked to databases of hospital admissions (to identify additional anomalies) and educational outcomes. Z-scores (signed number of SD actual score is above national average) were calculated to make outcome scores comparable across school years and across six assessed areas (personal development, communication and language, maths, knowledge of world, physical development andcreative development).Results2802 children without additional anomalies, 5 years old between 2006 and 2012, were included. Academic achievement was significantly below national average for all six assessed areas with z-scores ranging from −0.24 (95% CI −0.32 to −0.16) for knowledge of world to −0.31 (−0.38 to −0.23) for personal development. Differences were small with only a cleft lip but considerably larger with clefts involving the palate. 29.4% of children were documented as having special education needs (national rate 9.7%), which varied according to cleft type from 13.2% with cleft lip to 47.6% with bilateral cleft lip and palate.ConclusionsCompared with national average, 5-year-old children with an isolated oral cleft, especially those involving the palate, have significantly poorer academic achievement across all areas of learning. These outcomes reflect results of modern surgical techniques and multidisciplinary approach. Children with a cleft may benefit from extra academic support when starting school.

Linkage analysis in multiplex families has provisionally identified several genomic regions where genes influencing susceptibility to multiple sclerosis are likely to be located. It is anticipated that association mapping will provide a higher degree of resolution, but this more powerful approach is limited by the substantial genotyping effort required. Here, we describe the first use of DNA pooling to screen the whole genome for association in multiple sclerosis based on a 0.5 cM map of microsatellite markers and using four DNA pools derived from cases (n = 216), controls (n = 219) and trio families (n = 745 affected individuals and their 1490 parents). The 10 markers showing the greatest evidence for association with multiple sclerosis that emerge from this analysis include three from the HLA region on chromosome 6p (D6S1615, D6S2444 and TNFa), providing a positive control for the method, four from regions previously identified by linkage analysis in UK multiplex families (two mapping to chromosome 17q GCT6E11 and D17S1535; one to chromosome 1p GGAA30B06; and one to 19q D19S585), and three from novel sites with respect to linkage analysis (D1S1590 at 1q; D2S2739 at 2p; and D4S416 at 4q). Our results thus provide further supporting evidence for the candidature of 6p, 17q, 19q and 1p as regions encoding susceptibililty genes for multiple sclerosis. The protocol used in this UK-based study is now being extended to 18 additional sites in Europe in order to search for susceptibility genes shared between populations of common ancestry, as well as those that exert ethnically more restricted effects.