Novel ageing-biomarker discovery using data-intensive technologies

Ageing is accompanied by many visible characteristics. Other biological and physiological markers are also well-described e.g. loss of circulating sex hormones and increased inflammatory cytokines. Biomarkers for healthy ageing studies are presently predicated on existing knowledge of ageing traits. The increasing availability of data-intensive methods enables deep-analysis of biological samples for novel biomarkers. We have adopted two discrete approaches in MARK-AGE Work Package 7 for biomarker discovery; (1) microarray analyses and/or proteomics in cell systems e.g. endothelial progenitor cells or T cell ageing including a stress model; and (2) investigation of cellular material and plasma directly from tightly-defined proband subsets of different ages using proteomic, transcriptomic and miR array. The first approach provided longitudinal insight into endothelial progenitor and T cell ageing.This review describes the strategy and use of hypothesis-free, data-intensive approaches to explore cellular proteins, miR, mRNA and plasma proteins as healthy ageing biomarkers, using ageing models and directly within samples from adults of different ages. It considers the challenges associated with integrating multiple models and pilot studies as rational biomarkers for a large cohort study. From this approach, a number of high-throughput methods were developed to evaluate novel, putative biomarkers of ageing in the MARK-AGE cohort.

Spectrum of morphological and visual changes due to vitreomacular interface disorders encountered in a large consecutive cohort of patients

Aim: Identify the incidence of vitreomacular traction (VMT) and frequency of reduced vision in the absence of other coexisting macular pathology using a pragmatic classification system for VMT in a population of patients referred to the hospital eye service. Methods: A detailed survey of consecutive optical coherence tomography (OCT) scans was done in a high-throughput ocular imaging service to ascertain cases of vitreomacular adhesion (VMA) and VMT using a departmental classification system. Analysis was done on the stages of traction, visual acuity, and association with other macular conditions. Results: In total, 4384 OCT scan episodes of 2223 patients were performed. Two hundred and fourteen eyes had VMA/VMT, with 112 eyes having coexisting macular pathology. Of 102 patients without coexisting pathology, 57 patients had VMT grade between 2 and 8, with a negative correlation between VMT grade and number of Snellen lines (r= -0.61717). There was a distinct cutoff in visual function when VMT grade was higher than 4 with the presence of cysts and sub retinal separation and breaks in the retinal layers. Conclusions: VMT is a common encounter often associated with other coexisting macular pathology. We estimated an incidence rate of 0.01% of VMT cases with reduced vision and without coexisting macular pathology that may potentially benefit from intervention. Grading of VMT to select eyes with cyst formation as well as hole formation may be useful for targeting patients who are at higher risk of visual loss from VMT.

The prevalence of tympanic membrane and related middle ear pathology in children:a large longitudinal cohort study followed from birth to age ten

OBJECTIVE: To record with video-otoscopy the appearance of the tympanic membranes of a cross section of children aged 9 to 10 years. STUDY DESIGN: Cross-sectional study nested within an established longitudinal study of childhood development, the Avon Longitudinal Study of Parents and Children. SETTING: South West England, U.K. PARTICIPANTS: Approximately 6908 of 7261 children with ages ranging from 105 to 140 months born between April 1, 1991, and December 31, 1992, were examined by trained technicians with video-otoscopy. MAIN OUTCOME MEASURES: Two photographs were taken of each child's tympanic membranes to show the features of the pars tensa and the pars flaccida. RESULTS: In just less than three quarters of the children, both ears were normal. Retraction of the pars flaccida was present in 9.6% of children, and that of the pars tensa was present in 7.9%. Most of these changes were mild with few severe retractions. There were 15 cases of overt or suspected cholesteatoma. CONCLUSION: The tympanic membrane changes reflect most of the middle ear disease seen in 9- to 10-year-old children. The prevalence is low, and few children have serious disease at this stage.

Balance ability of 7 and 10 year old children in the population:results from a large UK birth cohort study

OBJECTIVE: The literature contains many reports of balance function in children, but these are often on atypical samples taken from hospital-based clinics and may not be generalisable to the population as a whole. The purpose of the present study is to describe balance test results from a large UK-based birth cohort study. METHODS: Data from the Avon Longitudinal Study of Parents and Children (ALSPAC) were analysed. A total of 5402 children completed the heel-to-toe walking test at age 7 years. At age 10 years, 6915 children underwent clinical tests of balance including beam-walking, standing heel-to-toe on a beam and standing on one leg. A proportion of the children returned to the clinic for retesting within 3 months allowing test-retest agreement to be measured. RESULTS: Frequency distributions for each of the balance tests are given. Correlations between measures of dynamic balance at ages 7 and 10 years were weak. The static balance of 10 year old children was found to be poorer with eyes closed than with eyes open, and poorer in boys than in girls for all measures. Balance on one leg was poorer than heel-to-toe balance on a beam. A significant learning effect was found when first and second attempts of the tests were compared. Measures of static and dynamic balance appeared independent. Consistent with previous reports in the literature, test-retest reliability was found to be low. CONCLUSIONS: This study provides information about the balance ability of children aged 7 and 10 years and provides clinicians with reference data for balance tests commonly used in the paediatric clinic.

Influence of birth cohort on age of onset cluster analysis in bipolar I disorder

PURPOSE: Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database. METHODS: The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared. RESULTS: There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups. CONCLUSION: These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.

Pathway to clozapine use:a comparison between a patient cohort from New Zealand and a cohort from the United Kingdom

Background and Objective: Clozapine has been available since the early 1990s. Studies continue to demonstrate its superior efficacy in treatment-resistant schizophrenia. Despite this, numerous studies show under-utilisation, delayed access and reluctance by psychiatrists to prescribe clozapine. This retrospective cross-sectional study compared the prescribing of clozapine in two adult cohorts under the care of large public mental health services in Auckland (New Zealand) and Birmingham (United Kingdom) on 31 March 2007. Method: Time from first presentation to clozapine initiation, prior antipsychotics trialled and antipsychotic co-prescribing were compared. Data included demographics, psychiatric diagnosis, co-morbid conditions, year of first presentation, admissions and pharmacological treatment (clozapine dose, start date, prior antipsychotics, co-prescribed antipsychotic). Results: Overall, 664 people were prescribed clozapine (402 Auckland; 262 Birmingham); mean daily dose of 384 mg (Auckland) and 429 mg (Birmingham). 53 % presented after 1990 and the average duration of time before starting clozapine was significantly longer in the Birmingham cohort (6.5 vs. 5.3 years) but this reduced in both cohorts to a 1-year mean in those presenting within the last 3 years. The average number of antipsychotics trialled pre-clozapine for those presenting since 1990 was significantly higher in the Birmingham cohort (4.3 vs. 3.1) but in both cohorts this similarly reduced in those presenting within the last 3 years. Antipsychotic co-prescribing was significantly higher in the Birmingham cohort (22.9 vs. 10.7 %). Conclusions: There is evidence that access to clozapine has improved over time in both cohorts, with a reduction in the duration between presentation and initiation of clozapine and number of different antipsychotics trialled pre-clozapine. These are very positive findings in terms of optimising outcomes with clozapine and are possibly due to the impact of guideline recommendations, increasing clinician, consumer and carer knowledge, and experience with clozapine and funding changes. © 2014 Springer International Publishing.

Prevalence and risk factors for mild and high-frequency bilateral sensorineural hearing loss at age 11 years old:a UK prospective cohort study

OBJECTIVE: This study aimed to assess prevalence and risk factors for mild/high-frequency bilateral sensorineural hearing loss within a UK population of children at age 11 years. DESIGN: Prospective birth cohort study. STUDY SAMPLE: Repeat hearing thresholds were measured in 5032 children, as part of the Avon Longitudinal Study of Parents and Children (ALSPAC) at age 7, 9, and 11 years. Pregnancy, birth, and early medical history were obtained prospectively through parental questionnaires and medical records. RESULTS: Twenty children had mild and seven had high-frequency bilateral sensorineural hearing loss, giving a combined prevalence of 0.5% (95% CI 0.4-0.8%). These children were more likely than the rest of the study sample to have been admitted to hospital at 6-18 months (OR 2.7, 95% CI 1.00-7.30). Parents of these children were more likely to have suspected a hearing problem when the children were 3 years old (OR 2.4, 95% CI 1.05-5.60). CONCLUSIONS: This is the first UK prospective cohort study to investigate the prevalence of mild and high-frequency hearing loss. This study, which has the advantage of a large sample size and repeat hearing measures over a four year period, reports lower prevalence values than US cross-sectional studies.