Commutative Schur Rings Over Symmetric Groups II: The Case n=6

We determine the commutative Schur rings over $S_6$ that contain the sum of all the transpositions in $S_6$. There are eight such types (up to conjugacy), of which four have the set of all the transpositions as a principal set of the Schur ring

The genes for mouse globin and the post-transcriptional control of their expression

In this work I have investigated the possible role of gene reiteration, amplification or deletion, as a means of regulating the expression of the globin gene during tissue differentiation in the mouse. This has employed a probe of complementary DNA (CDNA) prepared by copying reticulocyte 9S RNA using avian myeloblastosis virus reverse transcriptase. Since this RNA contains the messenger RNAs for alpha and beta globin, the cDNA produced is complementary to the alpha and beta globin genes. The fidelity of this cDNA said its use as a probe for globin sequences in DNA and RNA are rigorously justified. The rates of hybridisation of this probe to whole mouse embryo DNA, mouse erythroid DNA from 14 day foetal livers, and mouse germ line DNA from sperm are compared. The small corrections required for the size differences of the hybridising molecules, said the slight mismatching in the cDNA are estimated. The study demonstrates that there are 1-2 copies of the globin alpha and beta genes in all tissues studied, and thus mechstnisms other than gene amplification or deletion are required to explain the control of globin gene expression. The existence of post-transcriptional mechanisms by which this regulation may occur was then investigated. The first of these is the translational role of the poly(A) segment found on the 3' of eukaryotic mRNAs. This segment was removed from reticulocyte 9S RNA, using polynucleotide phosphorylase . Several experiments were performed to demonstrate the absence of the poly(A) sequence from the mRNA. The ability of this mRNA to code for alpha and beta globin chain synthesis in several cell-free protein synthesising systems was compared with intact mRNA. The results demonstrate that the poly(A) segment is not required for efficient initiation, elongation, termination or reinitiation of protein synthesis in a cell-free system. The role of the poly (A) sequence in determining the nuclear metabolism of globin RNA was then investigated. Low levels of globin RNA sequences were detected using cDNA in the nucleus of several non-erythroid tissues, adult mouse brain and liver, and a cultured lymphoma cell line, L5178Y. Very much lower levels of globin RNA sequences were detected in the cytoplasm of these cells. In contrast, in the erythroid 14 day foetal mouse liver, the amounts of globin RNA sequences found in the cytoplasm were very much higher than that in the nucleus. This indicates the operation of a post-transcriptional regulatory mechanism, whereby the nuclear said cytoplasmic levels of globin RNA sequences are regulated independently. However, this mechanism appears not to be mediated through association of nuclear globin RNA sequences with poly(A) since in both erythroid and non-erythroid tissues, where the fraction of total cell globin RNA sequences in the cytoplasm varies considerably, the proportion of polyadenylated nuclear globin RNA sequences is the same. At the present time, the possible functions of this low-level transcription of the globin gene in non-erythroid tissues are unclear

Genome-wide DNA methylation in mixed ancestry individuals with diabetes and prediabetes from South Africa

Aims. To conduct a genome-wide DNA methylation in individuals with type 2 diabetes, individuals with prediabetes, and control mixed ancestry individuals from South Africa. Methods. We used peripheral blood to perform genome-wide DNA methylation analysis in 3 individuals with screen detected diabetes, 3 individuals with prediabetes, and 3 individuals with normoglycaemia from the Bellville South Community, Cape Town, South Africa, who were age-, gender-, body mass index-, and duration of residency-matched. Methylated DNA immunoprecipitation (MeDIP) was performed by Arraystar Inc. (Rockville, MD, USA). Results. Hypermethylated DMRs were 1160 (81.97%) and 124 (43.20%), respectively, in individuals with diabetes and prediabetes when both were compared to subjects with normoglycaemia. Our data shows that genes related to the immune system, signal transduction, glucose transport, and pancreas development have altered DNA methylation in subjects with prediabetes and diabetes. Pathway analysis based on the functional analysis mapping of genes to KEGG pathways suggested that the linoleic acid metabolism and arachidonic acid metabolism pathways are hypomethylated in prediabetes and diabetes. Conclusions. Our study suggests that epigenetic changes are likely to be an early process that occurs before the onset of overt diabetes. Detailed analysis of DMRs that shows gradual methylation differences from control versus prediabetes to prediabetes versus diabetes in a larger sample size is required to confirm these findings

Comparing the performance of the novel FAMCAT algorithms and established case-finding criteria for familial hypercholesterolaemia in primary care

Objective Familial hypercholesterolaemia (FH) is a common inherited disorder causing premature coronary heart disease (CHD) and death. We have developed the novel Familial Hypercholesterolaemia Case Ascertainment Tool (FAMCAT 1) case-finding algorithm for application in primary care, to improve detection of FH. The performance of this algorithm was further improved by including personal history of premature CHD (FAMCAT 2 algorithm). This study has evaluated their performance, at 95% specificity, to detect genetically confirmed FH in the general population. We also compared these algorithms to established clinical case-finding criteria.Methods Prospective validation study, in 14 general practices, recruiting participants from the general adult population with cholesterol documented. For 260 participants with available health records, we determined possible FH cases based on FAMCAT thresholds, Dutch Lipid Clinic Network (DLCN) score, Simon-Broome criteria and recommended cholesterol thresholds (total cholesterol >9.0 mmol/L if ≥30 years or >7.5 mmol/L if ≤30 years), using clinical data from electronic and manual extraction of patient records and family history questionnaires. The reference standard was genetic testing. We examined detection rate (DR), sensitivity and specificity for each case-finding criteria.Results At 95% specificity, FAMCAT 1 had a DR of 27.8% (95% CI 12.5% to 50.9%) with sensitivity of 31.2% (95% CI 11.0% to 58.7%); while FAMCAT 2 had a DR of 45.8% (95% CI 27.9% to 64.9%) with sensitivity of 68.8% (95% CI 41.3% to 89.0%). DLCN score ≥6 points yielded a DR of 35.3% (95% CI 17.3% to 58.7%) and sensitivity of 37.5% (95% CI 15.2% to 64.6%). Using recommended cholesterol thresholds resulted in DR of 28.0% (95% CI 14.3% to 47.6%) with sensitivity of 43.8% (95% CI 19.8% to 70.1%). Simon-Broome criteria had lower DR 11.3% (95% CI 6.0% to 20.0%) and specificity 70.9% (95% CI 64.8% to 76.5%) but higher sensitivity of 56.3% (95% CI 29.9% to 80.2%).Conclusions In primary care, in patients with cholesterol documented, FAMCAT 2 performs better than other case-finding criteria for detecting genetically confirmed FH, with no prior clinical review required for case finding

Cost-Effectiveness of Screening Algorithms for Familial Hypercholesterolaemia in Primary Care

Although familial hypercholesterolemia (FH) screening within primary care is considered cost-effective, which screening approach is cost-effective has not been established. This study determines the cost-effectiveness of six case-finding strategies for screening of electronic health records to identify index patients who have genetically confirmed monogenic FH in English primary care. A decision tree was constructed to represent pathways of care for each approach (FH Case Identification Tool (FAMCAT) versions 1 and 2, cholesterol screening, Dutch Lipid Clinic Network (DLCN), Simon Broome criteria, no active screening). Clinical effectiveness was measured as the number of monogenic FH cases identified. Healthcare costs for each algorithm were evaluated from an NHS England perspective over a 12 week time horizon. The primary outcome was the incremental cost per additional monogenic FH case identified (ICER). FAMCAT2 was found to dominate (cheaper and more effective) cholesterol and FAMCAT1 algorithms, and extendedly dominate DLCN. The ICER for FAMCAT2 vs. no active screening was 8111 GBP (95% CI: 4088 to 14,865), and for Simon Broome vs. FAMCAT2 was 74,059 GBP (95% CI: −1,113,172 to 1,697,142). Simon Broome found the largest number of FH cases yet required 102 genetic tests to identify one FH patient. FAMCAT2 identified fewer, but only required 23 genetic tests

Risk of cardiovascular disease outcomes in primary care subjects with familial hypercholesterolaemia: A cohort study

Background and aims: Familial hypercholesterolaemia (FH) is a known major cause of premature heart disease. However, the risks of atherosclerotic disease in other vascular regions are less known. We determined the risk of major cardiovascular disease (CVD) outcomes associated with clinical FH.Methods: In a retrospective cohort study (1 January, 1999 to 22 July, 2016), we randomly-matched 14,097 UK subjects with clinical FH diagnoses or characteristics (Simon-Broome definite or Dutch Lipid Clinic Score >8) to 42,506 subjects without FH by age, sex, general practice. We excluded those with CVD at baseline. Incident rates for coronary heart disease (CHD), stroke or transient ischaemic attack (TIA) and peripheral vascular disease (PVD) were estimated. Cox proportional hazards regression, stratified on matched-pairs, determined adjusted hazards ratios (HR) for incident CVD.Results: During follow-up (median 13.8 years), incidence rates (95% CI) of CVD (per 1000 person-years) were 25.6 (24.8–26.3) in FH and 2.9 (2.8–3.1) in non-FH subjects. The risk of CHD, stroke/TIA and PVD was higher in FH compared to non-FH subjects: CHD (HR 10.63, 95% CI 9.82–11.49), stroke/TIA (HR 6.74, 95% CI 5.84–7.77), PVD (HR 7.17, 95% CI 6.08–8.46). The risk of CVD was greater in those with FH characteristics (HR 13.52, 95% CI 12.48–14.65) than those with clinical diagnoses (HR 1.66, 95% CI 1.42–1.93).Conclusions: In addition to the recognised increased risk of CHD, subjects with FH have greatly elevated risk of stroke/TIA and PVD. This emphasises need for early diagnosis and preventive interventions beyond CHD, to reduce CVD risk in these individuals

Case-finding and genetic testing for familial hypercholesterolaemia in primary care

Objective: Familial Hypercholesterolaemia (FH) is a common inherited disorder causing premature heart disease and death. We have developed novel case-finding algorithms (FAMCAT version 1 & 2) for application in primary care, to improve detection of FH and have evaluated their performance, at 95% specificity, to detect genetically-confirmed FH in the general population. We also compared these algorithms to established clinical case-finding criteria. Methods: Prospective validation study, in 14 general practices, recruiting participants from the general adult population with cholesterol documented. For 260 participants with available health records, we determined possible FH cases based on FAMCAT thresholds, Dutch Lipid Clinic Network (DLCN) score, Simon-Broome criteria and national recommended cholesterol thresholds (total cholesterol > 9.0 mmol/L if ≥30 years or > 7.5 mmol/L i

Sex differences in cardiovascular morbidity associated with familial hypercholesterolaemia: A retrospective cohort study of the UK Simon Broome register linked to national hospital records

Background and aims: The UK Simon Broome (SB) familial hypercholesterolaemia (FH) register previously reported 3-fold higher standardised mortality ratio for cardiovascular disease (CVD) in women compared to men from 2009 to 2015. Here we examined sex differences in CVD morbidity in FH by national linkage of the SB register with Hospital Episode Statistics (HES).Methods: Of 3553 FH individuals in the SB register (aged 20-79 years at registration), 2988 (52.5% women) had linked HES records. Standardised Morbidity Ratios (SMbR) compared to an age and sex-matched UK general practice population were calculated [95% confidence intervals] for first CVD hospitalisation in HES (a composite of coronary heart disease (CHD), myocardial infarction (MI), stable or unstable angina, stroke, TIA, peripheral vascular disease (PVD), heart failure, coronary revascularisation interventions).Results: At registration, men had significantly (p50 years, SMbR was 33% higher in women than men (6.11 [5.57-6.70] vs 4.59 [4.08-5.15]).Conclusions: Excess CVD morbidity due to FH remains markedly elevated in women at all ages, but especially those aged 30-50 years. This highlights the need for earlier diagnosis and optimisation of lipid-lowering risk factor management for all FH patients, with particular attention to young women with FH

Improving identification of familial hypercholesterolaemia in primary care: Derivation and validation of the familial hypercholesterolaemia case ascertainment tool (FAMCAT)

Objective: Heterozygous familial hypercholesterolaemia (FH) is a common autosomal dominant disorder. The vast majority of affected individuals remain undiagnosed, resulting in lost opportunities for preventing premature heart disease. Better use of routine primary care data offers an opportunity to enhance detection. We sought to develop a new predictive algorithm for improving identification of individuals in primary care who could be prioritised for further clinical assessment using established diagnostic criteria. Methods: Data were analysed for 2,975,281 patients with total or LDL-cholesterol measurement from 1 Jan 1999 to 31 August 2013 using the Clinical Practice Research Datalink (CPRD). Included in this cohort study were 5050 documented cases of FH. Stepwise logistic regression was used to derive optimal multivariate prediction models. Model performance was assessed by its discriminatory accuracy (area under receiver operating curve [AUC]). Results: The FH prediction model (FAMCAT), consisting of nine diagnostic variables, showed high discrimination (AUC 0.860, 95% CI 0.848–0.871) for distinguishing cases from non-cases. Sensitivity analysis demonstrated no significant drop in discrimination (AUC 0.858, 95% CI 0.845–0.869) after excluding secondary causes of hypercholesterolaemia. Removing family history variables reduced discrimination (AUC 0.820, 95% CI 0.807–0.834), while incorporating more comprehensive family history recording of myocardial infraction significantly improved discrimination (AUC 0.894, 95% CI 0.884–0.904). Conclusion: This approach offers the opportunity to enhance detection of FH in primary care by identifying individuals with greatest probability of having the condition. Such cases can be prioritised for further clinical assessment, appropriate referral and treatment to prevent premature heart disease