Genealogical typing of Neisseria meningitidis

Despite the increasing popularity of multilocus sequence typing (MLST), the most appropriate method for characterizing bacterial variation and facilitating epidemiological investigations remains a matter of debate. Here, we propose that different typing schemes should be compared on the basis of their power to infer clonal relationships and investigate the utility of sequence data for genealogical reconstruction by exploiting new statistical tools and data from 20 housekeeping loci for 93 isolates of the bacterial pathogen Neisseria meningitidis. Our analysis demonstrated that all but one of the hyperinvasive isolates established by multilocus enzyme electrophoresis and MLST were grouped into one of six genealogical lineages, each of which contained substantial variation. Due to the confounding effect of recombination, evolutionary relationships among these lineages remained unclear, even using 20 loci. Analyses of the seven loci in the standard MLST scheme using the same methods reproduced this classification, but were unable to support finer inferences concerning the relationships between the members within each complex

Changes in serogroup and genotype prevalence among carried meningococci in the United Kingdom during vaccine implementation.

BACKGROUND: Herd immunity is important in the effectiveness of conjugate polysaccharide vaccines against encapsulated bacteria. A large multicenter study investigated the effect of meningococcal serogroup C conjugate vaccine introduction on the meningococcal population. METHODS: Carried meningococci in individuals aged 15-19 years attending education establishments were investigated before and for 2 years after vaccine introduction. Isolates were characterized by multilocus sequence typing, serogroup, and capsular region genotype and changes in phenotypes and genotypes assessed. RESULTS: A total of 8462 meningococci were isolated from 47 765 participants (17.7%). Serogroup prevalence was similar over the 3 years, except for decreases of 80% for serogroup C and 40% for serogroup 29E. Clonal complexes were associated with particular serogroups and their relative proportions fluctuated, with 12 statistically significant changes (6 up, 6 down). The reduction of ST-11 complex serogroup C meningococci was probably due to vaccine introduction. Reasons for a decrease in serogroup 29E ST-254 meningococci (from 1.8% to 0.7%) and an increase in serogroup B ST-213 complex meningococci (from 6.7% to 10.6%) were less clear. CONCLUSIONS: Natural fluctuations in carried meningococcal genotypes and phenotypes a can be affected by the use of conjugate vaccines, and not all of these changes are anticipatable in advance of vaccine introduction

Molecular epidemiology of meningococcal disease in England and Wales 1975–1995, before the introduction of serogroup C conjugate vaccines

A comprehensive meningococcal vaccine is yet to be developed. In the absence of a vaccine that immunizes against the serogroup B capsular polysaccharide, this can only be achieved by targeting subcapsular antigens, and a number of outer-membrane proteins (OMPs) are under consideration as candidates. A major obstacle to the development of such a vaccine is the antigenic diversity of these OMPs, and obtaining population data that accurately identify and catalogue these variants is an important component of vaccine design. The recently proposed meningococcal molecular strain-typing scheme indexes the diversity of two OMPs, PorA and FetA, that are vaccine candidates, as well as the capsule and multilocus sequence type. This scheme was employed to survey 323 meningococci isolated from invasive disease in England and Wales from 1975 to 1995, before the introduction of meningococcal conjugated serogroup C polysaccharide vaccines in 1999. The eight-locus typing scheme provided high typeability (99.4 %) and discrimination (Simpson's diversity index 0.94–0.99). The data showed cycling of meningococcal genotypes and antigenic types in the absence of planned interventions. Notwithstanding high genetic and antigenic diversity, most of the isolates belonged to one of seven clonal complexes, with 11 predominant strain types. Combinations of PorA and FetA, chosen on the basis of their prevalence over time, generated vaccine recipes that included protein variants found in 80 % or more of the disease isolates for this time period. If adequate immune responses can be generated, these results suggest that control of meningococcal disease with relatively simple protein component vaccines may be possible

The Knee Clinical Assessment Study – CAS(K). A prospective study of knee pain and knee osteoarthritis in the general population: baseline recruitment and retention at 18 months

BACKGROUND: Selective non-participation at baseline (due to non-response and non-consent) and loss to follow-up are important concerns for longitudinal observational research. We investigated these matters in the context of baseline recruitment and retention at 18 months of participants for a prospective observational cohort study of knee pain and knee osteoarthritis in the general population. METHODS: Participants were recruited to the Knee Clinical Assessment Study – CAS(K) – by a multi-stage process involving response to two postal questionnaires, consent to further contact and medical record review (optional), and attendance at a research clinic. Follow-up at 18-months was by postal questionnaire. The characteristics of responders/consenters were described for each stage in the recruitment process to identify patterns of selective non-participation and loss to follow-up. The external validity of findings from the clinic attenders was tested by comparing the distribution of WOMAC scores and the association between physical function and obesity with the same parameters measured directly in the target population as whole. RESULTS: 3106 adults aged 50 years and over reporting knee pain in the previous 12 months were identified from the first baseline questionnaire. Of these, 819 consented to further contact, responded to the second questionnaire, and attended the research clinics. 776 were successfully followed up at 18 months. There was evidence of selective non-participation during recruitment (aged 80 years and over, lower socioeconomic group, currently in employment, experiencing anxiety or depression, brief episode of knee pain within the previous year). This did not cause significant bias in either the distribution of WOMAC scores or the association between physical function and obesity. CONCLUSION: Despite recruiting a minority of the target population to the research clinics and some evidence of selective non-participation, this appears not to have resulted in significant bias of cross-sectional estimates. The main effect of non-participation in the current cohort is likely to be a loss of precision in stratum-specific estimates e.g. in those aged 80 years and over. The subgroup of individuals who attended the research clinics and who make up the CAS(K) cohort can be used to accurately estimate parameters in the reference population as a whole. The potential for selection bias, however, remains an important consideration in each subsequent analysis

The Clinical Assessment Study of the Hand (CAS-HA): a prospective study of musculoskeletal hand problems in the general population

<p>Abstract</p> <p>Background</p> <p>Pain in the hand affects an estimated 12–21% of the population, and at older ages the hand is one of the most common sites of pain and osteoarthritis. The association between symptomatic hand osteoarthritis and disability in everyday life has not been studied in detail, although there is evidence that older people with hand problems suffer significant pain and disability. Despite the high prevalence of hand problems and the limitations they cause in older adults, little attention has been paid to the hand by health planners and policy makers. We plan to conduct a prospective, population-based, observational cohort study designed in parallel with our previously reported cohort study of knee pain, to describe the course of musculoskeletal hand problems in older adults and investigate the relative merits of different approaches to classification and defining prognosis.</p> <p>Methods/Design</p> <p>All adults aged 50 years and over registered with two general practices in North Staffordshire will be invited to take part in a two-stage postal survey. Respondents to the survey who indicate that they have experienced hand pain or problems within the previous 12 months will be invited to attend a research clinic for a detailed assessment. This will consist of clinical interview, hand assessment, screening test of lower limb function, digital photography, plain x-rays, anthropometric measurement and brief self-complete questionnaire. All consenting clinic attenders will be followed up by (i) general practice medical record review, (ii) repeat postal questionnaire at 18-months, and (iii) repeat postal questionnaire at 3 years.</p> <p>Discussion</p> <p>This paper describes the protocol for the Clinical Assessment Study of the Hand (CAS-HA), a prospective, population-based, observational cohort study of community-dwelling older adults with hand pain and hand problems based in North Staffordshire.</p

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio