Kathleen A. Daly

Epidemiology, natural history, and risk factors: Panel report from the Ninth International Research Conference on Otitis Media

The 2007 Recent Advances in Otitis Media Research Conference Panel Report provides an update on otitis media (OM) research published from 2003 to 2007. This report summarizes important trends in disease incidence and prevalence, describes established and newly identified risk factors for acute and chronic OM and OM with effusion, and conveys information on newly discovered genetic factors. In this report, researchers have described declining rates of OM diagnosis, antibiotic prescriptions, offices visits for OM, and middle ear surgery since the licensure and routine use of pneumococcal conjugate vaccine in infants. The panel report also recommends short and long term goals for current and future OM research.

Chronic and Recurrent Otitis Media: A Genome Scan for Susceptibility Loci

Otitis media (OM) is the most common childhood disease. Almost all children experience at least one episode, but morbidity is greatest in children who experience chronic/recurrent OM (COME/ROM). There is mounting evidence that COME/ROM clusters in families and exhibits substantial heritability. Subjects who had tympanostomy tube surgery for COME/ROM (probands) and their families were recruited for the present study, and an ear examination was performed, without knowledge of the subjects history, to determine presence of OM sequelae. In addition, tympanometric testing was performed at three frequencies (226, 630 or 710, and 1,400 Hz) to detect abnormal middle-ear mechanics, and hearing was screened at 20 dB for the speech frequencies. Of these families, 121 had at least two individuals who had received the diagnosis of COME/ROM (364 affected and genotyped individuals), of whom 238 affected and informative relative pairs were used for analyses. Single-point nonparametric linkage analysis provided evidence of linkage of COME/ROM to chromosome 10q at marker D10S212 (LOD 3.78; P=3.0 x 10(-5)) and to chromosome 19q at marker D19S254 (LOD 2.61; P=5.3 x 10(-4)). Analyses conditional on support for linkage at chromosomes 10q and 19q resulted in a significant increase in LOD score support on chromosome 3p (between markers D3S4545 and D3S1259). These results suggest that risk of COME/ROM is determined by interactions between genes that reside in several candidate regions of the genome and are probably modulated by other environmental risk factors.

Cellular telephone use and risk of intratemporal facial nerve tumor.

Objectives/Hypothesis Microwave radiation exposure from cellular telephone use has been implicated in the development of intracranial tumors. The intratemporal facial nerve (IFN) is exposed to higher levels of cellular telephone radiation than intracranial tissues. The purpose of the study was to determine whether cellular telephone use is associated with an increased risk of IFN tumors.

Otoacoustic emissions and tympanometry screening among 0-5 year olds

Objectives To determine the rate of otitis media (OM)‐associated transient evoked otoacoustic emissions (TEOAE) screening failure in a sample of preschool children, to evaluate concordance between TEOAE and tympanometry, to investigate risk factors for TEOAE failure, and to determine agreement between TEOAE failure and physician findings at referral.

Epidemiology, natural history, and risk factors

This report marks the 20th anniversary of the first Epidemiology and Natural History Panel Report. Epidemiology has become an increasingly important discipline in the study of otitis media (OM) over the past 2 decades. The objective of this report is to provide a critical review of the epidemiologic literature that has appeared since the 1995 Panel Report, and to identify short-term and long-term goals relevant to OM epidemiology, natural history, and risk factors.

Evaluation of 15 functional candidate genes for association with chronic otitis media with effusion and/or recurrent otitis media (COME/ROM).

DNA sequence variants in genes involved in the innate immune response and secondary response to infection may confer susceptibility to chronic otitis media with effusion and/or recurrent otitis media (COME/ROM). We evaluated single nucleotide polymorphisms (SNPs) in 15 functional candidate genes. A total of 99 SNPs were successfully genotyped on the Sequenom platform in 142 families (618 subjects) from the Minnesota COME/ROM Family Study. Data were analyzed for association with COME/ROM using the Generalized Disequilibrium Test (GDT). Sex and age at exam were adjusted as covariates, relatedness was accounted for, and genotype differences from all phenotypically discordant relative pairs were utilized to measure the evidence of association between COME/ROM and each SNP. SNP rs2735733 in the region of the mucin 5, subtypes A/C gene (MUC5AC) exhibited nominal evidence for association with COME/ROM (P = 0.002). Two additional SNPs from this region had P values<0.05. Other variants exhibiting associations with COME/ROM at P<0.05 included the SCN1B SNP rs8100085 (P = 0.013), SFTPD SNP rs1051246 (P = 0.039) and TLR4 SNP rs2770146 (P = 0.038). However, none of these associations replicated in an independent sample of COME/ROM families. The candidate gene variants examined do not appear to make a major contribution to COME/ROM susceptibility, despite a priori evidence from functional or animal model studies for a role in COME/ROM pathology.

Tympanic membrane perforations and tympanostomy tubes

Tympanoplasty and tympanostomy tubes were developed at the same time and have dramatically changed the treatment of chronic middle ear disease. One hundred forty-nine children who had tubes inserted between ages 6 months and 8 years for chronic otitis media with effusion have been prospectively followed up for an average of 4 years. Fourteen percent developed tympanic membrane perforations. No preoperative factor completely predicted the development of perforation. a majority of the perforations closed spontaneously. Three ears had noncontiguous observations of perforations during follow-up. The implications of these findings are discussed with respect to tympanoplasty.

Evaluation of newborn screening bloodspot-based genetic testing as second tier screen for bedside newborn hearing screening

Purpose: Bedside newborn hearing screening is highly successful in identifying deaf or hard-of-hearing infants. However, newborn hearing screening protocols have high loss to follow-up rates. We propose that bloodspot-based genetic testing for GJB2 alleles can provide a means for rapid confirmation in a subset of infants who fail bedside newborn hearing screening.Methods: We performed a case-control study comparing the prevalence of common GJB2 mutations from deidentified bloodspots designated as “refer” by newborn hearing screening and contemporaneously selected randomly chosen controls designated as “pass.” Between March 2006 and December 2007, 2354 spots were analyzed for common alleles, c.35delG, c.167delT, c.235delC, and p.V37I in GJB2 with a subset reanalyzed by conventional Sanger sequencing to search for additional alleles.Results: The prevalence of biallelic GJB2 mutations in bloodspots from infants who referred by newborn hearing screening is approximately 1 in 50 (23/1177). In contrast, one bloodspot from an infant who passed newborn hearing screening was identified to harbor biallelic GJB2 mutations.Conclusions: These findings show that when a newborn refers by newborn hearing screening, there is a significant chance that GJB2-related hearing loss is present. Bloodspot-based genetic testing for common GJB2 alleles should be considered as second tier testing for bedside newborn hearing screening.

Significant linkage at chromosome 19q for otitis media with effusion and/or recurrent otitis media (COME/ROM)

BackgroundIn previous analyses, we identified a region of chromosome 19 as harboring a susceptibility locus for chronic otitis media with effusion and/or recurrent otitis media (COME/ROM). Our aim was to further localize the linkage signal and ultimately identify the causative variant or variants. We followed up our previous linkage scan with dense SNP genotyping across in a 5 Mb region. A total of 607 individuals from 139 families, including 159 affected sib pairs and 62 second-degree affected relative pairs, were genotyped at 1,091 SNPs. We carried out a nonparametric linkage analysis, modeling marker-to-marker linkage disequilibrium.ResultsThe maximum log of the odds (LOD) score increased to 3.75 (P = 1.6 × 10-5) at position 63.4 Mb, with a LOD-1 support interval between 61.6 Mb and 63.8 Mb, providing significant evidence of linkage between this region and COME/ROM. The support interval contains over 90 known genes, including several genes involved in the inflammasome protein complex, a key regulator of the innate immune response to harmful exogenous or endogenous stimuli. Parametric linkage analysis suggests that for a sib of an affected individual, the recurrence risk of COME/ROM due to this linkage region is twice the recurrence risk in the population. We examined potential associations between the SNPs genotyped in this region and COME/ROM, however none provided evidence for association.ConclusionThis study has refined the 19q region of linkage with COME/ROM, and association results suggest that the linkage signal may be due to rare variants.

Otitis media and associations with overweight status in toddlers

INTRODUCTION Otitis media (OM) is a significant disease that affects nearly all children early in life. Recently, childhood overweight has become an epidemic. Past research has demonstrated that a history of OM is related to food preferences and overweight through proposed physiological mechanisms. The purpose of this study was to explore the relationship between recurrent OM (ROM)/tympanostomy tube treatment and overweight status. METHODS Data were analyzed from a prospective cohort of mothers and children recruited from 1991-1996 from a local health maintenance organization. ROM and tympanostomy tube status were obtained through a combination of physical exam and medical record abstraction. ROM and tympanostomy tube status were analyzed as categorical variables with weight-for-length (WFL) data from well child checks. Chi-square and logistic regression for univariate and multivariate analyses were performed. RESULTS 11.4% of children had a WFL measure at two years of age ≥ 95 th percentile. Those children with a history of tympanostomy tube treatment had a significantly increased risk of having a WFL ≥ 95 th percentile after controlling for birth weight, maternal prenatal smoking, maternal education, and family income (OR 3.32, 95% CI 1.43-7.72). The alternative hypothesis that children with larger WFL at two month of age would have a greater number of OM episodes by two years of age was not significant. CONCLUSION The findings of this study are consistent with the hypothesis and prior research that OM treated with tympanostomy tubes is associated with overweight status.