Association of SNPs in LCP1 and CTIF with hearing in 11 year old children:findings from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort and the G-EAR consortium

BACKGROUND: The genetic basis of hearing loss in humans is relatively poorly understood. In recent years, experimental approaches including laboratory studies of early onset hearing loss in inbred mouse strains, or proteomic analyses of hair cells or hair bundles, have suggested new candidate molecules involved in hearing function. However, the relevance of these genes/gene products to hearing function in humans remains unknown. We investigated whether single nucleotide polymorphisms (SNPs) in the human orthologues of genes of interest arising from the above-mentioned studies correlate with hearing function in children. METHODS: 577 SNPs from 13 genes were each analysed by linear regression against averaged high (3, 4 and 8 kHz) or low frequency (0.5, 1 and 2 kHz) audiometry data from 4970 children in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth-cohort at age eleven years. Genes found to contain SNPs with low p-values were then investigated in 3417 adults in the G-EAR study of hearing. RESULTS: Genotypic data were available in ALSPAC for a total of 577 SNPs from 13 genes of interest. Two SNPs approached sample-wide significance (pre-specified at p = 0.00014): rs12959910 in CBP80/20-dependent translation initiation factor (CTIF) for averaged high frequency hearing (p = 0.00079, β = 0.61 dB per minor allele); and rs10492452 in L-plastin (LCP1) for averaged low frequency hearing (p = 0.00056, β = 0.45 dB). For low frequencies, rs9567638 in LCP1 also enhanced hearing in females (p = 0.0011, β = -1.76 dB; males p = 0.23, β = 0.61 dB, likelihood-ratio test p = 0.006). SNPs in LCP1 and CTIF were then examined against low and high frequency hearing data for adults in G-EAR. Although the ALSPAC results were not replicated, a SNP in LCP1, rs17601960, is in strong LD with rs9967638, and was associated with enhanced low frequency hearing in adult females in G-EAR (p = 0.00084). CONCLUSIONS: There was evidence to suggest that multiple SNPs in CTIF may contribute a small detrimental effect to hearing, and that a sex-specific locus in LCP1 is protective of hearing. No individual SNPs reached sample-wide significance in both ALSPAC and G-EAR. This is the first report of a possible association between LCP1 and hearing function.

The dyslexia candidate locus on 2p12 is associated with general cognitive ability and white matter structure

Independent studies have shown that candidate genes for dyslexia and specific language impairment (SLI) impact upon reading/language-specific traits in the general population. To further explore the effect of disorder-associated genes on cognitive functions, we investigated whether they play a role in broader cognitive traits. We tested a panel of dyslexia and SLI genetic risk factors for association with two measures of general cognitive abilities, or IQ, (verbal and non-verbal) in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (N>5,000). Only the MRPL19/C2ORF3 locus showed statistically significant association (minimum P = 0.00009) which was further supported by independent replications following analysis in four other cohorts. In addition, a fifth independent sample showed association between the MRPL19/C2ORF3 locus and white matter structure in the posterior part of the corpus callosum and cingulum, connecting large parts of the cortex in the parietal, occipital and temporal lobes. These findings suggest that this locus, originally identified as being associated with dyslexia, is likely to harbour genetic variants associated with general cognitive abilities by influencing white matter structure in localised neuronal regions.

Textbook on contract law

This edition of the guide to the law of contract takes account of the implications of Internet contracting and includes discussion of the Consumer Protection (Distance Selling) Regulations 2000. Where appropriate, reference is made, for reasons of comparison, to the principles contained in thePrinciples of European Contract Law (PECL) and the UNIDROIT Principles of International Commercial Contracts.;Significant developments in contract law, both statutory and case law, are discussed, including the Contracts (Rights of Third Parties) Act 1999, the Electronic Communications Act 2000 andthe House of Lords' decisions in Alfred McAlpine Construction Ltd v Panatown Ltd and Attorney General V Blake. Other important decisions covered in this revised edition are Royal Bank of Scotland v Etridge, Barclays Bank Plc v Coleman, Barclays Bank Plc v Boulter, Avon Insurance v Swire, Zanzibar vBritish Aerospace (Lancsaster House) Ltd and Nutt v Read. In addition, there is discussion of the Unfair Terms in Consumer Contracts Regulations 1999 and the European Commission's Review of the Unfair Terms Directive, as well as coverage of Director General of Fair Trading v First National Bank. Other decisions on illegality, onerous terms, constructionand repudiation of contract are included.

Prevalence and characteristics of spontaneous tinnitus in 11-year-old children

OBJECTIVE: To estimate the prevalence of spontaneous tinnitus in 11-year-old children. DESIGN: A prospective UK population-based study. STUDY SAMPLE: A total of 7092 children from the Avon longitudinal study of parents and children (ALSPAC) who attended the hearing session at age 11 years and answered questions about tinnitus. RESULTS: We estimated the prevalence of any spontaneous tinnitus as 28.1% (95% CI 27.1, 29.2%), and the prevalence of 'clinically significant' tinnitus as 3.1% (95% CI 2.7, 3.5%). Children were less likely to have clinically significant tinnitus if the tinnitus was 'soft' rather than 'loud' and if continuous rather than intermittent. Clinical significance was more likely if the tinnitus occurred more than once a week. Neither pitch nor length of history were important determinants of clinical significance. Small increases in mean hearing threshold (of up to 2.3 dB HL) were associated with clinically significant tinnitus. CONCLUSIONS: Although the prevalence of any tinnitus in 11-year-old children appears high, the small proportion in which this was found to be clinically significant implies that this does not necessarily indicate a large unmet clinical demand. We would expect approximately one child per class of 30 to have clinically significant tinnitus which is, by definition, problematic.

Prevalence and risk factors for reduced sound tolerance (hyperacusis) in children

OBJECTIVE: To estimate the prevalence of reduced sound tolerance (hyperacusis) in a UK population of 11-year-old children and examine the association of early life and auditory risk factors with report of hyperacusis. DESIGN: A prospective UK population-based study. STUDY SAMPLE: A total of 7097 eleven-year-old children within the Avon longitudinal study of parents and children (ALSPAC) were asked about sound tolerance; hearing and middle-ear function was measured using audiometry, otoacoustic emissions, and tympanometry. Information on neonatal risk factors and socioeconomic factors were obtained through parental questionnaires. RESULTS: 3.7% (95% CI 3.25, 4.14) children reported hyperacusis. Hyperacusis report was less likely in females (adj OR 0.64, 95% CI 0.49, 0.85), and was more likely with higher maternal education level (adj OR 1.72, 95% CI 1.08, 2.72) and with readmission to hospital in first four weeks (adj OR 1.98, 95% CI 1.20, 3.25). Report of hyperacusis was associated with larger amplitude otoacoustic emissions but with no other auditory factors. CONCLUSIONS: The prevalence of hyperacusis in the population of 11-year-old UK children is estimated to be 3.7%. It is more common in boys.

Glue ear, hearing loss and IQ:an association moderated by the child's home environment

BACKGROUND: Glue ear or otitis media with effusion (OME) is common in children and may be associated with hearing loss (HL). For most children it has no long lasting effects on cognitive development but it is unclear whether there are subgroups at higher risk of sequelae. OBJECTIVES: To examine the association between a score comprising the number of times a child had OME and HL (OME/HL score) in the first four/five years of life and IQ at age 4 and 8. To examine whether any association between OME/HL and IQ is moderated by socioeconomic, child or family factors. METHODS: Prospective, longitudinal cohort study: the Avon Longitudinal Study of Parents and Children (ALSPAC). 1155 children tested using tympanometry on up to nine occasions and hearing for speech (word recognition) on up to three occasions between age 8 months and 5 years. An OME/HL score was created and associations with IQ at ages 4 and 8 were examined. Potential moderators included a measure of the child's cognitive stimulation at home (HOME score). RESULTS: For the whole sample at age 4 the group with the highest 10% OME/HL scores had performance IQ 5 points lower [95% CI -9, -1] and verbal IQ 6 points lower [95% CI -10, -3] than the unaffected group. By age 8 the evidence for group differences was weak. There were significant interactions between OME/HL and the HOME score: those with high OME/HL scores and low 18 month HOME scores had lower IQ at age 4 and 8 than those with high OME/HL scores and high HOME scores. Adjusted mean differences ranged from 5 to 8 IQ points at age 4 and 8. CONCLUSIONS: The cognitive development of children from homes with lower levels of cognitive stimulation is susceptible to the effects of glue ear and hearing loss.

Balance ability in 7- and 10-year-old children:associations with prenatal lead and cadmium exposure and with blood lead levels in childhood in a prospective birth cohort study

OBJECTIVES: Most studies reporting evidence of adverse effects of lead and cadmium on the ability to balance have been conducted in high-exposure groups or have included adults. The effects of prenatal exposure have not been well studied, nor have the effects in children been directly studied. The aim of the study was to identify the associations of lead (in utero and in childhood) and cadmium (in utero) exposure with the ability to balance in children aged 7 and 10 years. DESIGN: Prospective birth cohort study. PARTICIPANTS: Maternal blood lead (n=4285) and cadmium (n=4286) levels were measured by inductively coupled plasma mass spectrometry in women enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) during pregnancy. Child lead levels were measured in a subsample of 582 of ALSPAC children at age 30 months. MAIN OUTCOME MEASURES: Children completed a heel-to-toe walking test at 7 years. At 10 years, the children underwent clinical tests of static and dynamic balance. Statistical analysis using SPSS V.19 included logistic regression modelling, comparing categories of ≥ 5 vs <5 µg/dL for lead, and ≥ 1 vs <1 µg/L for cadmium. RESULTS: Balance at age 7 years was not associated with elevated in utero lead or cadmium exposure (adjusted OR for balance dysfunction: Pb 1.01 (95% CI 0.95 to 1.01), n=1732; Cd 0.95 (0.77 to 1.20), n=1734), or with elevated child blood lead level at age 30 months (adjusted OR 0.98 (0.92 to 1.05), n=354). Similarly, neither measures of static nor dynamic balance at age 10 years were associated with in utero lead or cadmium exposure, or child lead level. CONCLUSIONS: These findings do not provide any evidence of an association of prenatal exposure to lead or cadmium, or lead levels in childhood, on balance ability in children. Confirmation in other cohorts is needed.

Prenatal alcohol exposure and childhood balance ability:findings from a UK birth cohort study

OBJECTIVE: To investigate the association of prenatal alcohol exposure with balance in10-year-old children. DESIGN: Population-based prospective longitudinal study. SETTING: Former Avon region of UK (Southwest England). PARTICIPANTS: 6915 children from the Avon Longitudinal Study of Parents and Children who had a balance assessment at age 10 and had data on maternal alcohol consumption. OUTCOME MEASURES: 3 composite balance scores: dynamic balance (beam-walking), static balance eyes open, static balance eyes closed (heel-to-toe balance on a beam and standing on one leg, eyes open or closed). RESULTS: Most mothers (95.5%) consumed no-to-moderate amounts (3-7 glasses/week) of alcohol during pregnancy. Higher total-alcohol consumption was associated with maternal-social advantage, whereas binge drinking (≥4 units/day) and abstinence were associated with maternal social disadvantage. No evidence was found of an adverse effect of maternal-alcohol consumption on childhood balance. Higher maternal-alcohol use during pregnancy was generally associated with better offspring outcomes, with some specific effects appearing strong (static balance eyes open and moderate total alcohol exposure at 18 weeks, adjusted OR 1.23 (95% CI 1.01 to 1.49); static balance eyes closed and moderate total alcohol exposure at 18 weeks, adjusted OR 1.25 (95% CI 1.06 to 1.48). Similar results were found for both paternal and postnatal maternal alcohol exposure. A Mendelian-randomization approach was used to estimate the association between maternal genotype and offspring balance using the non-synonymous variant rs1229984*A (ADH1B) to proxy for lower maternal alcohol consumption; no strong associations were found between this genotype/proxy and offspring balance. CONCLUSIONS: No evidence was found to indicate that moderate maternal alcohol consumption in this population sample had an adverse effect on offspring balance at age 10. An apparent beneficial effect of higher total maternal alcohol consumption on offspring balance appeared likely to reflect residual confounding.

Prevalence and audiological features in carriers of GJB2 mutations, c.35delG and c.101T>C (p.M34T), in a UK population study

OBJECTIVES: To determine the carrier rate of the GJB2 mutation c.35delG and c.101T>C in a UK population study; to determine whether carriers of the mutation had worse hearing or otoacoustic emissions compared to non-carriers. DESIGN: Prospective cohort study. SETTING: University of Bristol, UK. PARTICIPANTS: Children in the Avon Longitudinal Study of Parents and Children. 9202 were successfully genotyped for the c.35delG mutation and c.101>T and classified as either carriers or non-carriers. OUTCOME MEASURES: Hearing thresholds at age 7, 9 and 11 years and otoacoustic emissions at age 9 and 11. RESULTS: The carrier frequency of the c.35delG mutation was 1.36% (95% CI 1.13 to 1.62) and c.101T>C was 2.69% (95% CI 2.37 to 3.05). Carriers of c.35delG and c.101T>C had worse hearing than non-carriers at the extra-high frequency of 16 kHz. The mean difference in hearing at age 7 for the c.35delG mutation was 8.53 dB (95% CI 2.99, 14.07) and 12.57 dB at age 9 (95% CI 8.10, 17.04). The mean difference for c.101T>C at age 7 was 3.25 dB (95% CI -0.25 to 6.75) and 7.61 dB (95% CI 4.26 to 10.96) at age 9. Otoacoustic emissions were smaller in the c.35delG mutation carrier group: at 4 kHz the mean difference was -4.95 dB (95% CI -6.70 to -3.21) at age 9 and -3.94 dB (95% CI -5.78 to -2.10) at age 11. There was weak evidence for differences in otoacoustic emissions amplitude for c.101T>C carriers. CONCLUSION: Carriers of the c.35delG mutation and c.101T>C have worse extra-high-frequency hearing than non-carriers. This may be a predictor for changes in lower-frequency hearing in adulthood. The milder effects observed in carriers of c.101T>C are in keeping with its classification as a mutation causing mild/moderate hearing loss in homozygosity or compound heterozygosity.

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.

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.

Dizziness in 10 year old children:an epidemiological study

OBJECTIVE: Current data about the prevalence and characteristics of dizziness in the paediatric population is very limited and the generalisability of extant studies to the UK population has not been explored. Our study aims to provide a robust estimate of the prevalence of dizziness in 10 year old children in the UK, to describe the characteristics of this dizziness and to explore whether this dizziness is socially patterned. METHODS: Data from the Avon Longitudinal Study of Parents and Children (ALSPAC) was analysed (N=13,988). A total of 6965 of these children attended for a balance assessment session at age 10. Those who reported rotary vertigo were interviewed about their symptoms. Logistic regression was used to explore whether dizziness at age 10 is socially patterned. RESULTS: A total of 400 children reported rotary vertigo, giving a prevalence estimate of 5.7% [CI 5.2, 6.3%]. 13.1-20.6% of children reported experiencing their dizziness between 1 and 4 times a week (depending on the symptom). 51.5% of children had to stop what they were doing because of the dizziness making them feel unwell. A total of 60% of children reported headache as an accompanying symptom, tentatively suggesting a diagnosis of migraine, although there was no association between reports of headache and a maternal family history of migraine. 20.3% of children with dizziness also reported tinnitus and 17.3% reported that their hearing changed when they were dizzy. CONCLUSIONS: Dizziness in 10 year old children is not uncommon and in about half limits current activities. Rotary vertigo is commonly accompanied by dizziness of another description and also by headache. There is no evidence that dizziness at this age is socially patterned.

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.