Change on the Revised Hearing Handicap Inventory and associated factors: results from a longitudinal cohort study.

OBJECTIVE: Describe how the Revised Hearing Handicap Inventory (RHHI) changes over time and determine associated factors. DESIGN: Data were from a community-based cohort study. Linear regression models were used to estimate mean baseline and final RHHI scores and change (final minus baseline score). Logistic regression models were used to determine factors associated with substantial RHHI change, defined as ±6 points. Factors included baseline age, sex, race, hearing aid use, and baseline pure-tone average (PTA; 0.5, 1.0, 2.0, 4.0 kHz, worse ear). STUDY SAMPLE: This study included 583 participants (mean age: 66.4 [SD 9.1] years; 59.9% female; 14.2% Minority race) with a mean follow-up time of 7.6 (SD 4.9) years. RESULTS: Baseline and final RHHI scores were 7.9 and 9.2 points, corresponding to an average 1.3-point increase in hearing difficulty over time. Most participants (65.4%) did not show substantial RHHI change, whereas 21.4% and 13.2% experienced substantial increase and decrease, respectively. In separate multivariable models, PTA and hearing aid use were associated with substantial increase in hearing difficulty, and PTA was associated with substantial decrease. CONCLUSIONS: The average RHHI change was relatively small. Hearing aid use and PTA were associated with RHHI change.

Prevalence of self-reported hearing difficulty on the Revised Hearing Handicap Inventory and associated factors.

BACKGROUND: Hearing loss is common in aging adults and is an important public health concern. Self-reported measures of hearing difficulty are often used in research and clinical practice, as they capture the functional impacts of hearing loss on individuals. However, little research has evaluated the prevalence or factors associated with self-reported hearing difficulty. Therefore, the purpose of this study was to determine the prevalence of self-reported hearing difficulty, measured by the Revised Hearing Handicap Inventory (RHHI), and associated factors. METHODS: This study was conducted in a community-based cohort study based in Charleston, SC. We determined the prevalence of RHHI self-reported hearing difficulty (score ≥ 6 points) and evaluated associated factors with logistic regression models. Results are presented as odds ratios (OR) with corresponding 95% confidence intervals (95% CI). RESULTS: There were 1558 participants included in this study (mean age 63.7 [SD 14.4], 56.9% female, 20.0% Minority race). The prevalence of RHHI self-reported hearing difficulty was 48.8%. In a multivariable model, older age (per + 1 year; OR 0.97 [95% CI 0.96, 0.98]), Minority (vs. White) race (OR 0.68 [95% CI 0.49, 0.94]), and speech-in-noise scores that are better than predicted (OR 0.99 [95% CI 0.98, 1.00]) were associated with lower odds of RHHI self-reported hearing difficulty. Furthermore, female (vs. male) sex (OR 1.39 [95% CI 1.03, 1.86]), higher PTA in the worse ear (per + 1 dB; OR 1.10 [95% CI 1.09, 1.12]), more comorbid conditions (vs. 0; 1 condition: OR 1.50 [95% CI 1.07, 2.11]; 2 conditions: OR 1.96 [95% CI 1.32, 2.93]; 3 + conditions: OR 3.00 [95% CI 1.60, 5.62]), noise exposure (OR 1.54 [95% CI 1.16, 2.03]), bothersome tinnitus (OR 2.16 [95% CI 1.59, 2.93]), and more depressive symptoms (OR 1.04 [95% CI 1.01, 1.07]) were associated with higher odds of RHHI self-reported hearing difficulty. CONCLUSIONS: The prevalence of RHHI self-reported hearing difficulty is high, and associated factors included demographics, audiometric hearing and other hearing-related factors, and physical and mental health. The RHHI likely captures functional impacts of hearing loss that are not captured by audiometry alone. Study findings can support the correct interpretation of the RHHI in research and clinical settings.

Agreement between audiometric hearing loss and self-reported hearing difficulty on the Revised Hearing Handicap Inventory differs by demographic factors.

BACKGROUND: New standardised measures of self-reported hearing difficulty can be validated against audiometric hearing loss. This study reports the influence of demographic factors (age, sex, race and socioeconomic position (SEP)) on the agreement between audiometric hearing loss and self-reported hearing difficulty. METHODS: Participants were 1558 adults (56.9% female; 20.0% racial minority; mean age 63.7 (SD 14.1) years) from the Medical University of South Carolina Longitudinal Cohort Study of Age-Related Hearing Loss (1988-current). Audiometric hearing loss was defined as the average of pure-tone thresholds at frequencies 0.5, 1.0, 2.0 and 4.0 kHz >25 dB HL in the worse ear. Self-reported hearing difficulty was defined as ≥6 points on the Revised Hearing Handicap Inventory (RHHI) or RHHI screening version (RHHI-S). We report agreement between audiometric hearing loss and the RHHI(-S), defined by sensitivity, specificity, accuracy, positive predictive value, negative predictive value and observed minus predicted prevalence. Estimates were stratified to age group, sex, race and SEP proxy. RESULTS: The prevalence of audiometric hearing loss and self-reported hearing difficulty were 49.0% and 48.8%, respectively. Accuracy was highest among participants aged <60 (77.6%) versus 60-70 (71.4%) and 70+ (71.9%) years, for white (74.6%) versus minority (68.0%) participants and was similar by sex and SEP proxy. Generally, agreement of audiometric hearing loss and RHHI(-S) self-reported hearing difficulty differed by age, sex and race. CONCLUSIONS: Relationships of audiometric hearing loss and self-reported hearing difficulty vary by demographic factors. These relationships were similar for the full (RHHI) and screening (RHHI-S) versions of this tool.

Effects of age and noise exposure history on auditory nerve response amplitudes: A systematic review, study, and meta-analysis.

Auditory nerve (AN) function has been hypothesized to deteriorate with age and noise exposure. Here, we perform a systematic review of published studies and find that the evidence for age-related deficits in AN function is largely consistent across the literature, but there are inconsistent findings among studies of noise exposure history. Further, evidence from animal studies suggests that the greatest deficits in AN response amplitudes are found in noise-exposed aged mice, but a test of the interaction between effects of age and noise exposure on AN function has not been conducted in humans. We report a study of our own examining differences in the response amplitude of the compound action potential N1 (CAP N1) between younger and older adults with and without a self-reported history of noise exposure in a large sample of human participants (63 younger adults 18-30 years of age, 103 older adults 50-86 years of age). CAP N1 response amplitudes were smaller in older than younger adults. Noise exposure history did not appear to predict CAP N1 response amplitudes, nor did the effect of noise exposure history interact with age. We then incorporated our results into two meta-analyses of published studies of age and noise exposure history effects on AN response amplitudes in neurotypical human samples. The meta-analyses found that age effects across studies are robust (r = -0.407), but noise exposure effects are weak (r = -0.152). We conclude that noise exposure effects may be highly variable depending on sample characteristics, study design, and statistical approach, and researchers should be cautious when interpreting results. The underlying pathology of age-related and noise-induced changes in AN function are difficult to determine in living humans, creating a need for longitudinal studies of changes in AN function across the lifespan and histological examination of the AN from temporal bones collected post-mortem.

Effects of Age and Noise Exposure History on Auditory Nerve Response Amplitudes: A Systematic Review, Study, and Meta-Analysis.

Auditory nerve (AN) function has been hypothesized to deteriorate with age and noise exposure. Here, we perform a systematic review of published studies and find that the evidence for age-related deficits in AN function is largely consistent across the literature, but there are inconsistent findings among studies of noise exposure history. Further, evidence from animal studies suggests that the greatest deficits in AN response amplitudes are found in noise-exposed aged mice, but a test of the interaction between effects of age and noise exposure on AN function has not been conducted in humans. We report a study of our own examining differences in the response amplitude of the compound action potential N1 (CAP N1) between younger and older adults with and without a self-reported history of noise exposure in a large sample of human participants (63 younger adults 18-30 years of age, 103 older adults 50-86 years of age). CAP N1 response amplitudes were smaller in older than younger adults. Noise exposure history did not appear to predict CAP N1 response amplitudes, nor did the effect of noise exposure history interact with age. We then incorporated our results into two meta-analyses of published studies of age and noise exposure history effects on AN response amplitudes in neurotypical human samples. The meta-analyses found that age effects across studies are robust (r=-0.407), but noise-exposure effects are weak (r=-0.152). We conclude that noise-exposure effects may be highly variable depending on sample characteristics, study design, and statistical approach, and researchers should be cautious when interpreting results. The underlying pathology of age-related and noise-induced changes in AN function are difficult to determine in living humans, creating a need for longitudinal studies of changes in AN function across the lifespan and histological examination of the AN from temporal bones collected post-mortem.

The Revised Hearing Handicap Inventory and Pure-Tone Average Predict Hearing Aid Use Equally Well.

PURPOSE: This study aimed to (a) compare the Revised Hearing Handicap Inventory (RHHI) and pure-tone average (PTA) in their abilities to predict hearing aid use and (b) report the optimal cut-point values on the RHHI and PTA that predict hearing aid use. METHOD: Participants were from a community-based cohort study. We evaluated the ability of the RHHI and PTA as (a) continuous variables and (b) binary variables characterized by the optimal cut point determined by the Youden Index to predict hearing aid use. RHHI scores range from 0 to 72, and PTA was defined as averaged thresholds at frequencies 0.5, 1.0, 2.0, and 4.0 kHz in the worse ear. We used logistic regression models and receiver operating characteristic curves with corresponding concordance statistics (c-statistics) and 95% confidence intervals (CIs) to determine the predictive ability of models and chi-square tests to determine whether c-statistics were significantly different. RESULTS: This study included 581 participants (Mage = 72.9 [SD = 9.9] years; 59.9% female; 14.3% Minority race). The c-statistics for the RHHI (0.79, 95% CI [0.75, 0.83]) and PTA (0.81, 95% CI [0.78, 0.85]), as continuous variables, were not significantly different (p = .25). The optimal cut points for the RHHI and PTA to predict hearing aid use were 6 points and 32.5 dB HL, respectively. The c-statistics for the RHHI (0.72, 95% CI [0.68, 0.76]) and PTA (0.75, 95% CI [0.71, 0.79]), as binary variables, were not significantly different (p = .27). CONCLUSION: The RHHI and PTA are similar in their ability to predict hearing aid use.

Probability Distributions for Associations Between Cognitive Screening and Pure-tone Thresholds in Older Adults.

OBJECTIVES: Lower general cognitive function is frequently reported in older adults with elevated pure-tone thresholds. Here, we examined reason(s) for this association, including whether this relationship is dependent on the frequency range or extent of hearing loss and cognitive screening performance. DESIGN: Linear regression was used to examine associations between better-ear pure-tone thresholds and Mini-Mental Status Exam (MMSE) performance in a cross-sectional sample of relatively healthy older adults (N = 508; 68% women, 60-89+ years; M age = 72). Quantile regression was also used to identify the ranges of 0.5 and 4.0 kHz thresholds and MMSE scores where these variables exhibited significant associations. RESULTS: MMSE scores and pure-tone thresholds exhibited small but significant associations, particularly for better-ear 0.5 kHz thresholds. This hearing threshold and cognitive screening association was present among participants with better hearing, including the oldest older adults. There was limited evidence for mediating health condition effects on this association. An item analysis of the MMSE revealed that the MMSE and pure-tone threshold associations were largely due to the delayed recall item of the MMSE. CONCLUSIONS: Together, the small effect results are consistent with the extant literature and suggest that there are multiple reasons for modest pure-tone threshold and cognitive screening performance associations.

Metabolic and Sensory Components of Age-Related Hearing Loss.

Age-related hearing loss is a multifactorial condition with effects of aging and environmental exposures that contribute to cochlear pathologies. Metabolic hearing loss involves declines in the endocochlear potential, which broadly reduce cochlear amplification of low-level sounds. Sensory hearing loss involves damage to outer hair cells that may eliminate amplification, especially for high-frequency sounds. A novel approach was developed to estimate the extent of metabolic and sensory components (in dB) for an individual, by combining hearing loss profiles to optimally approximate their hearing thresholds (audiogram). This approach was validated using estimates of metabolic and sensory hearing loss from retrospective datasets including gerbils, cross-sectional and longitudinal audiograms from older adults, a measure of speech recognition in noise, and histopathology case reports. Simulation results showed that well-approximated audiograms can produce accurate metabolic and sensory estimates. Estimates of metabolic and sensory components of age-related hearing loss differentiated gerbils with known strial and/or sensory pathologies based on age and exposures. For older adults, metabolic estimates consistently increased with age and were associated with poorer speech recognition in noise, while sensory estimates were related to sex and noise exposure differences. Histopathology case reports (with audiograms) that described strial and outer hair cell pathology in temporal bones from older donors showed significant differences in metabolic and sensory estimates, respectively. The results support the view that audiograms include information that can be used to estimate the metabolic and sensory components of age-related hearing loss.

Evaluating the Relationship Between Olfactory Function and Loneliness in Community-Dwelling Individuals: A Cross-sectional Study.

BACKGROUND: Olfactory dysfunction (OD) has been reported to impact social interactions. However, the relationship between OD and loneliness has received little attention. The purpose of this study was to determine the association between OD and loneliness, controlling for patient factors. METHODS: Subjects without otolaryngic complaints were enrolled and olfactory function was assessed using: Sniffin' Sticks test to measure threshold, discrimination and identification (TDI), Questionnaire of Olfactory Disorders Negative Statements (QOD-NS) and 9 - item Olfactory-Visual Analogue Scale (VAS). Loneliness was assessed using the De Jong Gierveld (DJG) and University of California Los Angeles (UCLA) loneliness scales. Bivariate analysis was performed followed by regression analysis, controlling for confounders. RESULTS: In total, 221 subjects were included with a mean age of 50.5 years (range 20 to 93), 133 (60.2%) females and 161 (72.9%) white. Mean TDI score was 29.3 (7.0) and 49.5% of the cohort was dysosmic. Using DJG, 36.4% of the cohort were classified as lonely, whereas 35.0% were lonely using UCLA. Olfactory measures were significantly associated with DJG, including TDI (ß = -0.03, p = 0.050), olfactory discrimination (ß = -0.111, p = 0.005), QOD-NS (ß = 0.058, p < 0.001) and olfactory-VAS (ß = 0.032, p < 0.001). UCLA scores were significantly associated with QOD-NS (PR 1.061 [CI 1.018-1.107], p = 0.005) and olfactory-VAS scores (PR 1.027, [CI 1.007-1.049], p = 0.009). After controlling for confounders, the association between DJG and olfactory discrimination, as well as DJG and olfactory-VAS remained significant. CONCLUSIONS: In this community-based sample of older adults, both OD and loneliness were common. Those subjects with worse olfactory function were more likely to report loneliness. Further research is necessary to establish causality, as well as explore the role of depression.

Ranking subjects based on paired compositional data with application to age-related hearing loss subtyping.

Analysis approaches for single compositional data are well established; however, effective analysis strategies for paired compositional data remain to be investigated. The current project was motivated by studies of age-related hearing loss (presbyacusis), where subjects are classified into four audiometric phenotypes that need to be ranked within these phenotypes based on their paired compositional data. We address this challenge by formulating this problem as a classification problem and integrating a penalized multinomial logistic regression model with compositional data analysis approaches. We utilize Elastic Net for a penalty function, while considering average, absolute difference, and perturbation operators for compositional data. We applied the proposed approach to the presbyacusis study of 532 subjects with probabilities that each ear of a subject belongs to each of four presbyacusis subtypes. We further investigated the ranking of presbyacusis subjects using the proposed approach based on previous literature. The data analysis results indicate that the proposed approach is effective for ranking subjects based on paired compositional data.

A Community-Based Study on the Prevalence of Olfactory Dysfunction.

BACKGROUND: Olfactory dysfunction (OD) is common, affecting an estimated 13 million adults in the United States. Prior studies may underestimate OD prevalence due to use of brief smell identification tests or age-adjusted cutoff values, which concede that it is acceptable for older people to have a decreased sense of smell. OBJECTIVE: To determine OD prevalence in the healthy community when the goal and expectation is ideal olfactory function, rather than age-based population norms. Secondary goals were to explore factors associated with OD. METHODS: Subjects without otolaryngic complaints were recruited from the community surrounding the Medical University of South Carolina. Olfactory-specific information was collected, and olfactory function was assessed using the Sniffin' Sticks test (Burghardt, Wedel, Germany) to measure threshold, discrimination, and identification (TDI). OD was defined as a TDI score < 31. Bivariate analysis and linear regression were used to determine factors associated with OD. RESULTS: In total, 176 subjects were included with mean age of 52 years (range: 20-93), 111 (63%) female, and 127 (72%) white. Mean TDI score was 28.8 (6.9) and OD was present in 94 (53%) subjects. Multivariate linear regression revealed that TDI decreased an average of 1 point every 5 years. TDI was also associated with Mini-Mental Status Examination (MMSE) score, asthma, and gastroesophageal reflux disease. Threshold was associated with age, heart problems, and gastroesophageal reflux disease. Discrimination was associated with age and MMSE scores. Identification was associated with age, heart problems, and anxiety. CONCLUSIONS: In a community-based sample, OD affects greater than 50% of subjects. Aging impacts all aspects of olfaction, while the effects of factors such as asthma, MMSE scores, gastroesophageal reflux disease, heart problems, and anxiety may only be evident in specific olfactory subtests.

The Revised Hearing Handicap Inventory and Screening Tool Based on Psychometric Reevaluation of the Hearing Handicap Inventories for the Elderly and Adults.

OBJECTIVES: The present study evaluates the items of the Hearing Handicap Inventory for the Elderly and Hearing Handicap Inventory for Adults (HHIE/A) using Mokken scale analysis (MSA), a type of nonparametric item response theory, and develops updated tools with optimal psychometric properties. DESIGN: In a longitudinal study of age-related hearing loss, 1447 adults completed the HHIE/A and audiometric testing at baseline. Discriminant validity of the emotional consequences and social/situational effects subscales of the HHIE/A was assessed, and nonparametric item response theory was used to explore dimensionality of the items of the HHIE/A and to refine the scales. RESULTS: The HHIE/A items form strong unidimensional scales measuring self-perceived hearing handicap, but with a lack of discriminant validity of the two distinct subscales. Two revised scales, the 18-item Revised Hearing Handicap Inventory and the 10-item Revised Hearing Handicap Inventory-Screening, were developed from the common items of the original HHIE/A that met the assumptions of MSA. The items on both of the revised scales can be ordered in terms of increasing difficulty. CONCLUSIONS: The results of the present study suggest that the newly developed Revised Hearing Handicap Inventory and Revised Hearing Handicap Inventory-Screening are strong unidimensional, clinically informative measures of self-perceived hearing handicap that can be used for adults of all ages. The real-data example also demonstrates that MSA is a valuable alternative to classical psychometric analysis.

Age-Related Changes in Immune Cells of the Human Cochlea.

Age-related hearing loss is a chronic degenerative disorder affecting one in two individuals above the age of 75. Current population projections predict a steady climb in the number of older individuals making the search for interventions to prevent or reverse this disorder even more critical. There is growing acceptance that aberrant activity of resident or infiltrating immune cells, such as macrophages, is a major factor contributing to the onset and progression of age-related degenerative diseases. However, how macrophage populations and their functionally-driven morphological characteristics change with age in the human cochlea remains largely unknown. In this study, we employed immunohistochemical approaches along with confocal and super-resolution imaging, three-dimensional reconstructions, and quantitative analysis to determine age-related changes in macrophage numbers and morphology as well as interactions with other cell-types and structures of the auditory nerve and lateral wall in the human cochlea. In the cochlea of human ears from young and middle aged adults those macrophages in the auditory nerve assumed a worm-like structure in contrast to those in the spiral ligament or associated with the dense microvascular network in the stria vascularis which exhibited a highly ramified morphology. Macrophages in both the auditory nerve and cochlear lateral wall showed morphological alterations with age. The population of activated macrophages in the auditory nerve increased in cochleas obtained from older donors. Dual-immunohistochemical staining with macrophage, myelin, and neuronal markers revealed increased interactions of macrophages with the glial and neuronal components of the aged auditory nerve. These findings implicate the involvement of abnormal macrophage-glia interactions in age-related physiological and pathological alterations in the human cochlea. There is clearly a need to further investigate the contribution of macrophage-associated inflammatory dysregulation in human presbyacusis.

Development and Refinement of Patient-Reported Outcome Measures for Hearing: A Brief Introduction to Nonparametric Item Response Theory.

Purpose The purpose of this report was to demonstrate the value of incorporating nonparametric item response theory in the development and refinement of patient- reported outcome measures for hearing. Conclusions Nonparametric item response theory can be useful in the development and refinement of patient-reported outcome measures for hearing. These methods are particularly useful as an alternative to exploratory factor analysis to determine the number of underlying abilities or traits represented by a scale when the items have ordered-categorical responses.

Time From Hearing Aid Candidacy to Hearing Aid Adoption: A Longitudinal Cohort Study.

OBJECTIVES: Although many individuals with hearing loss could benefit from intervention with hearing aids, many do not seek or delay seeking timely treatment after the onset of hearing loss. There is limited data-based evidence estimating the delay in adoption of hearing aids with anecdotal estimates ranging from 5 to 20 years. The present longitudinal study is the first to assess time from hearing aid candidacy to adoption in a 28-year ongoing prospective cohort of older adults, with the additional goal of determining factors influencing delays in hearing aid adoption, and self-reported successful use of hearing aids. DESIGN: As part of a longitudinal study of age-related hearing loss, a wide range of demographic, biologic, and auditory measures are obtained yearly or every 2 to 3 years from a large sample of adults, along with family, medical, hearing, noise exposure, and hearing aid use histories. From all eligible participants (age ≥18; N = 1530), 857 were identified as hearing aid candidates either at baseline or during their participation, using audiometric criteria. Longitudinal data were used to track transition to hearing aid candidacy and hearing aid adoption. Demographic and hearing-related characteristics were compared between hearing aid adopters and nonadopters. Unadjusted estimated overall time (in years) to hearing aid adoption and estimated delay times were stratified by demographic and hearing-related factors and were determined using a time-to-event analysis (survival analysis). Factors influencing rate of adoption in any given time period were examined along with factors influencing successful hearing aid adoption. RESULTS: Age, number of chronic health conditions, sex, retirement status, and education level did not differ significantly between hearing aid adopters and nonadopters. In contrast, adopters were more likely than nonadopters to be married, of white race, have higher socioeconomic status, have significantly poorer higher frequency (2.0, 3.0, 4.0, 6.0, and 8.0 kHz) pure-tone averages, poorer word recognition in quiet and competing multi-talker babble, and reported more hearing handicap on the Hearing Handicap Inventory for the Elderly/Adults emotional and social subscales. Unadjusted estimation of time from hearing aid candidacy to adoption in the full participant cohort was 8.9 years (SE ± 0.37; interquartile range = 3.2-14.9 years) with statistically significant stratification for race, hearing as measured by low- and high-frequency pure-tone averages, keyword recognition in low-context sentences in babble, and the Hearing Handicap Inventory for the Elderly/Adults social score. In a subgroup analysis of the 213 individuals who adopted hearing aids and were assigned a success classification, 78.4% were successful. No significant predictors of success were found. CONCLUSIONS: The average delay in adopting hearing aids after hearing aid candidacy was 8.9 years. Nonwhite race and better speech recognition (in a more difficult task) significantly increased the delay to treatment. Poorer hearing and more self-assessed hearing handicap in social situations significantly decreased the delay to treatment. These results confirm the assumption that adults with hearing loss significantly delay seeking treatment with hearing aids.

Radiologic changes in the aging nasal cavity.

BACKGROUND: With an aging population, it is important to understand age-related anatomic changes in the nasal cavity and cribriform plate (CP) that may have clinical implications. METHODOLOGY: Computed tomography (CT) scans obtained for non-rhinologic conditions were divided into a young cohort (N=35, 18-34 years old) and an older adult cohort (N=32, 80-99 years old). Intranasal airspace volumes and bony anatomy of the CP were manually segmented using OsiriX software. The CP was assessed for mean Hounsfield Units (HU) and percentage of olfactory foramina. Deformation based morphometry (DBM) was then performed on the same cohort and correlated with manual measurements. RESULTS: Individual nasal cavity volumes increased 17-75% with age. Regression analysis of all scans revealed age to be the predominant variable influencing intranasal volume differences when controlling for sex and head size. Mean HU of the CP negatively correlated with age. No age-related differences in bone stenosis of olfactory foramina were identified. Automated DBM measurements of intranasal volumes, as well as CP and zygoma mean HU correlated with manual measurements. CONCLUSION: Older subjects have a global increase in intranasal volumes and diffuse bone density loss in the CP. The clinical impact of age-related anatomic changes in the nasal cavity and CP requires further investigation.

Whole exome sequencing in adult-onset hearing loss reveals a high load of predicted pathogenic variants in known deafness-associated genes and identifies new candidate genes.

BACKGROUND: Deafness is a highly heterogenous disorder with over 100 genes known to underlie human non-syndromic hearing impairment. However, many more remain undiscovered, particularly those involved in the most common form of deafness: adult-onset progressive hearing loss. Despite several genome-wide association studies of adult hearing status, it remains unclear whether the genetic architecture of this common sensory loss consists of multiple rare variants each with large effect size or many common susceptibility variants each with small to medium effects. As next generation sequencing is now being utilised in clinical diagnosis, our aim was to explore the viability of diagnosing the genetic cause of hearing loss using whole exome sequencing in individual subjects as in a clinical setting. METHODS: We performed exome sequencing of thirty patients selected for distinct phenotypic sub-types from well-characterised cohorts of 1479 people with adult-onset hearing loss. RESULTS: Every individual carried predicted pathogenic variants in at least ten deafness-associated genes; similar findings were obtained from an analysis of the 1000 Genomes Project data unselected for hearing status. We have identified putative causal variants in known deafness genes and several novel candidate genes, including NEDD4 and NEFH that were mutated in multiple individuals. CONCLUSIONS: The high frequency of predicted-pathogenic variants detected in known deafness-associated genes was unexpected and has significant implications for current diagnostic sequencing in deafness. Our findings suggest that in a clinic setting, efforts should be made to a) confirm key sequence results by Sanger sequencing, b) assess segregations of variants and phenotypes within the family if at all possible, and c) use caution in applying current pathogenicity prediction algorithms for diagnostic purposes. We conclude that there may be a high number of pathogenic variants affecting hearing in the ageing population, including many in known deafness-associated genes. Our findings of frequent predicted-pathogenic variants in both our hearing-impaired sample and in the larger 1000 Genomes Project sample unselected for auditory function suggests that the reference population for interpreting variants for this very common disorder should be a population of people with good hearing for their age rather than an unselected population.

Transient-Evoked Otoacoustic Emissions Reflect Audiometric Patterns of Age-Related Hearing Loss.

Distinct forms of age-related hearing loss are hypothesized based on evidence from animal models of aging, which are identifiable in human audiograms. The Sensory phenotype results from damage (e.g., excessive noise or ototoxic drugs) to outer hair cells and sometimes inner hair cells, producing large threshold increases predominately at high frequencies. The Metabolic phenotype results from a decline in endocochlear potential that can reduce outer hair cell motility throughout the cochlea, producing gradually sloping thresholds from lower to higher frequencies. Finally, the combined Metabolic + Sensory phenotype results in low-frequency losses similar to the Metabolic phenotype and high-frequency losses similar to the Sensory phenotype. Because outer hair cell function appears to be affected differently in each phenotype, this study used audiograms from 618 adults aged 50 to 93 years ( n = 1,208 ears) to classify phenotypes and characterize differences in transient-evoked otoacoustic emission (TEOAE) data. Significant phenotype differences were observed in frequency-band TEOAEs and configuration (intercept and slope), including large and broadly distributed TEOAE reductions for Metabolic and Metabolic + Sensory ears and more focused high-frequency TEOAE reductions for Sensory ears. These findings are consistent with metabolic declines that reduce cochlear amplification across a broad range of frequencies and more basally situated, high-frequency declines in sensory hearing loss. The results provide further validation for the classification of age-related hearing loss phenotypes based on audiograms and show human TEOAE declines that are highly consistent with animal models.

Novel Radiographic Assessment of the Cribriform Plate.

Background The cribriform plate (CP) is a common site of spontaneous cerebrospinal fluid (SCSF) leaks. Radiographic assessment of the anterior and lateral skull base has shown thinner bone in patients with SCSFs; however, prior assessment of the CP has required postmortem cadaver dissection. Objective To develop novel radiographic techniques to assess the anatomy of the CP. Methods Computed tomography (CT) scans were performed on cadaveric specimens. Bone density and anatomy of a predefined volume of interest of the posterior CP were assessed by two independent reviewers. CT assessment of olfactory foramina was also performed and validated using anatomic dissection of cadaver specimens. Results Interclass correlation coefficients (ICCs) for measuring the same volume of each CP was 0.96, confirming reproducible anatomic localization. Cadaver CPs had a mean Hounsfield units of 263, indicating a mix of bone and soft tissue, and ICC was 0.98, confirming reproducible radiographic measurements. Optimal CT estimates of bone composition of CPs averaged 85% (range 76% to 96%) compared to actual anatomic dissection which averaged 84% bone (range 74% to 91%, r = .690, P = .026). Conclusion Our novel, noninvasive CT method for assessing CP anatomy is reproducible and correlates with anatomic dissection assessing bone composition. The clinical implications of anatomic changes in the CP are an area for further study.

Joint modeling of multivariate hearing thresholds measured longitudinally at multiple frequencies.

Pure-tone thresholds are used to estimate hearing acuity and, when measured longitudinally, can characterize age-related changes in hearing. Measured at multiple-frequencies, multiple-irregular time points, for right and left ears, these longitudinal studies of age-related hearing loss produce data of inherent complexity due to: 1) multivariate outcomes at different frequencies; 2) longitudinal measurements taken at subject-specific time intervals; and 3) inter-ear correlations due to clustering and nesting. To address limitations in existing methods, we propose a multivariate generalized linear mixed model(mGLMM) and assess its performance. We demonstrate its application using a unique dataset from a cohort study of age-related hearing loss.