Accurate phenotypic classification and exome sequencing allow identification of novel genes and variants associated with adult-onset hearing loss.

Adult-onset progressive hearing loss is a common, complex disease with a strong genetic component. Although to date over 150 genes have been identified as contributing to human hearing loss, many more remain to be discovered, as does most of the underlying genetic diversity. Many different variants have been found to underlie adult-onset hearing loss, but they tend to be rare variants with a high impact upon the gene product. It is likely that combinations of more common, lower impact variants also play a role in the prevalence of the disease. Here we present our exome study of hearing loss in a cohort of 532 older adult volunteers with extensive phenotypic data, including 99 older adults with normal hearing, an important control set. Firstly, we carried out an outlier analysis to identify genes with a high variant load in older adults with hearing loss compared to those with normal hearing. Secondly, we used audiometric threshold data to identify individual variants which appear to contribute to different threshold values. We followed up these analyses in a second cohort. Using these approaches, we identified genes and variants linked to better hearing as well as those linked to worse hearing. These analyses identified some known deafness genes, demonstrating proof of principle of our approach. However, most of the candidate genes are novel associations with hearing loss. While the results support the suggestion that genes responsible for severe deafness may also be involved in milder hearing loss, they also suggest that there are many more genes involved in hearing which remain to be identified. Our candidate gene lists may provide useful starting points for improved diagnosis and drug development.

The Stria Vascularis in Mice and Humans Is an Early Site of Age-Related Cochlear Degeneration, Macrophage Dysfunction, and Inflammation.

Age-related hearing loss, or presbyacusis, is a common degenerative disorder affecting communication and quality of life for millions of older adults. Multiple pathophysiologic manifestations, along with many cellular and molecular alterations, have been linked to presbyacusis; however, the initial events and causal factors have not been clearly established. Comparisons of the transcriptome in the lateral wall (LW) with other cochlear regions in a mouse model (of both sexes) of "normal" age-related hearing loss revealed that early pathophysiological alterations in the stria vascularis (SV) are associated with increased macrophage activation and a molecular signature indicative of inflammaging, a common form of immune dysfunction. Structure-function correlation analyses in mice across the lifespan showed that the age-dependent increase in macrophage activation in the stria vascularis is associated with a decline in auditory sensitivity. High-resolution imaging analysis of macrophage activation in middle-aged and aged mouse and human cochleas, along with transcriptomic analysis of age-dependent changes in mouse cochlear macrophage gene expression, support the hypothesis that aberrant macrophage activity is an important contributor to age-dependent strial dysfunction, cochlear pathology, and hearing loss. Thus, this study highlights the SV as a primary site of age-related cochlear degeneration and aberrant macrophage activity and dysregulation of the immune system as early indicators of age-related cochlear pathology and hearing loss. Importantly, novel new imaging methods described here now provide a means to analyze human temporal bones in a way that had not previously been feasible and thereby represent a significant new tool for otopathological evaluation.SIGNIFICANCE STATEMENT Age-related hearing loss is a common neurodegenerative disorder affecting communication and quality of life. Current interventions (primarily hearing aids and cochlear implants) offer imperfect and often unsuccessful therapeutic outcomes. Identification of early pathology and causal factors is crucial for the development of new treatments and early diagnostic tests. Here, we find that the SV, a nonsensory component of the cochlea, is an early site of structural and functional pathology in mice and humans that is characterized by aberrant immune cell activity. We also establish a new technique for evaluating cochleas from human temporal bones, an important but understudied area of research because of a lack of well-preserved human specimens and difficult tissue preparation and processing approaches.

Soft classification and regression analysis of audiometric phenotypes of age-related hearing loss.

Age-related hearing loss has a complex etiology. Researchers have made efforts to classify relevant audiometric phenotypes, aiming to enhance medical interventions and improve hearing health. We leveraged existing pattern analyses of age-related hearing loss and implemented the phenotype classification via quadratic discriminant analysis (QDA). We herein propose a method for analyzing the exposure effects on the soft classification probabilities of the phenotypes via estimating equations. Under reasonable assumptions, the estimating equations are unbiased and lead to consistent estimators. The resulting estimator had good finite sample performances in simulation studies. As an illustrative example, we applied our proposed methods to assess the association between a dietary intake pattern, assessed as adherence scores for the dietary approaches to stop hypertension diet calculated using validated food-frequency questionnaires, and audiometric phenotypes (older-normal, metabolic, sensory, and metabolic plus sensory), determined based on data obtained in the Nurses' Health Study II Conservation of Hearing Study, the Audiology Assessment Arm. Our findings suggested that participants with a more healthful dietary pattern were less likely to develop the metabolic plus sensory phenotype of age-related hearing loss.

Extended High-Frequency Thresholds: Associations With Demographic and Risk Factors, Cognitive Ability, and Hearing Outcomes in Middle-Aged and Older Adults.

OBJECTIVES: This study had two objectives: to examine associations between extended high-frequency (EHF) thresholds, demographic factors (age, sex, race/ethnicity), risk factors (cardiovascular, smoking, noise exposure, occupation), and cognitive abilities; and to determine variance explained by EHF thresholds for speech perception in noise, self-rated workload/effort, and self-reported hearing difficulties. DESIGN: This study was a retrospective analysis of a data set from the MUSC Longitudinal Cohort Study of Age-related Hearing Loss. Data from 347 middle-aged adults (45 to 64 years) and 694 older adults (≥ 65 years) were analyzed for this study. Speech perception was quantified using low-context Speech Perception In Noise (SPIN) sentences. Self-rated workload/effort was measured using the effort prompt from the National Aeronautics and Space Administration-Task Load Index. Self-reported hearing difficulty was assessed using the Hearing Handicap Inventory for the Elderly/Adults. The Wisconsin Card Sorting Task and the Stroop Neuropsychological Screening Test were used to assess selected cognitive abilities. Pure-tone averages representing conventional and EHF thresholds between 9 and 12 kHz (PTA(9 - 12 kHz)) were utilized in simple linear regression analyses to examine relationships between thresholds and demographic and risk factors or in linear regression models to assess the contributions of PTA(9 - 12 kHz) to the variance among the three outcomes of interest. Further analyses were performed on a subset of individuals with thresholds ≤ 25 dB HL at all conventional frequencies to control for the influence of hearing loss on the association between PTA(9 - 12 kHz) and outcome measures. RESULTS: PTA(9 - 12 kHz) was higher in males than females, and was higher in White participants than in racial Minority participants. Linear regression models showed the associations between cardiovascular risk factors and PTA(9 - 12 kHz) were not statistically significant. Older adults who reported a history of noise exposure had higher PTA(9 - 12 kHz) than those without a history, while associations between noise history and PTA(9 - 12 kHz) did not reach statistical significance for middle-aged participants. Linear models adjusting for age, sex, race and noise history showed that higher PTA(9 - 12 kHz) was associated with greater self-perceived hearing difficulty and poorer speech recognition scores in noise for both middle-aged and older participants. Workload/effort was significantly related to PTA(9 - 12 kHz) for middle-aged, but not older, participants, while cognitive task performance was correlated with PTA(9 - 12 kHz) only for older participants. In general, PTA(9 - 12 kHz)did not account for additional variance in outcome measures as compared to conventional pure-tone thresholds, with the exception of self-reported hearing difficulties in older participants. Linear models adjusting for age and accounting for subject-level correlations in the subset analyses revealed no association between PTA(9 - 12 kHz)and outcomes of interest. CONCLUSIONS: EHF thresholds show age-, sex-, and race-related patterns of elevation that are similar to what is observed for conventional thresholds. The current results support the need for more research to determine the utility of adding EHF thresholds to routine audiometric assessment with middle-aged and older adults.

Computer-based Auditory Training by New Adult Cochlear Implant Recipients Is Associated With Durable Improvements in Cochlear Implant Quality of Life.

OBJECTIVE: The process of adapting to communicate with a cochlear implant (CI) is complex. The use of auditory training after cochlear implantation may help to facilitate improvements in postoperative speech recognition and quality-of-life outcomes in new adult CI recipients. However, the effectiveness of auditory training remains uncertain and long-term effects have not been examined in a large sample of new adult CI users. As such, the objective of this study was to examine the influence of common forms of auditory training on speech recognition and CI-related quality-of-life (CI-related QOL) outcomes at 1 year after cochlear implantation. We hypothesized that patients who reported use of computer-based auditory training (CBAT) would show improved speech and CIQOL-35 Profile scores at 1 year after activation of their implant, compared with their peers. DESIGN: This study was designed as a prospective study and was undertaken at a tertiary academic CI center. Participants included 114 adults undergoing cochlear implantation for bilateral hearing loss. Patients serially self-reported use of the following types of post-CI auditory training over their first-year postactivation: (1) face-to-face training (e.g., speech-language pathologist), (2) passive home-based training (e.g., listening to audiobooks), and (3) CBAT (e.g., self-directed software). Outcomes measures for this study included change in Consonant-Nucleus-Consonant phoneme (CNCp), CNC word (CNCw), AzBio sentences in quiet, and CIQOL-35 Profile global and domain scores from pre-CI to 12-mo post-CI. RESULTS: Of 114 patients, 94 (82.5%) used one or more auditory training resources. Of these, 19.3% used face-to-face training, 67.5% passive home-based training, and 46.5% CBAT. Of 114 patients, 73 had complete CIQOL data. At 12 mo, only CBAT use was associated with significantly greater improvements in global and all domain-specific CIQOL scores ( d -range = 0.72-0.87), compared with those not using CBAT. Controlling for demographics and use of multiple training resources, CBAT remained the strongest positive predictor of CIQOL improvement, with significant associations with global score (ß = 12.019[4.127,19.9]) and all domain scores at 12-mo post-CI: communication (ß = 11.937[2.456,21.318), emotional (ß = 12.293[1.827,22.759), entertainment (ß = 17.014[5.434,28.774), environment (ß = 13.771[1.814,25.727]), listening effort (ß = 12.523[2.798,22.248]), and social (ß = 18.114[7.403,28.826]). No significant benefits were noted with use of CBAT or any other form of auditory training and speech recognition scores at 12-mo post-CI ( d -range = -0.12-0.22). CONCLUSIONS: Auditory training with CBAT was associated with improved CI-related QOL outcomes at 12-mo post-CI. Given its availability and low cost, this study provides evidence to support using CBAT to improve real-world functional abilities in new adult CI recipients.

A Pragmatic Clinical Trial of Hearing Screening in Primary Care Clinics: Effect of Setting and Provider Encouragement.

OBJECTIVES: The prevalence of hearing loss increases with age. Untreated hearing loss is associated with poorer communication abilities and negative health consequences, such as increased risk of dementia, increased odds of falling, and depression. Nonetheless, evidence is insufficient to support the benefits of universal hearing screening in asymptomatic older adults. The primary goal of the present study was to compare three hearing screening protocols that differed in their level of support by the primary care (PC) clinic and provider. The protocols varied in setting (in-clinic versus at-home screening) and in primary care provider (PCP) encouragement for hearing screening (yes versus no). DESIGN: We conducted a multisite, pragmatic clinical trial. A total of 660 adults aged 65 to 75 years; 64.1% female; 35.3% African American/Black completed the trial. Three hearing screening protocols were studied, with 220 patients enrolled in each protocol. All protocols included written educational materials about hearing loss and instructions on how to complete the self-administered telephone-based hearing screening but varied in the level of support provided in the clinic setting and by the provider. The protocols were as follows: (1) no provider encouragement to complete the hearing screening at home, (2) provider encouragement to complete the hearing screening at home, and (3) provider encouragement and clinical support to complete the hearing screening after the provider visit while in the clinic. Our primary outcome was the percentage of patients who completed the hearing screening within 60 days of a routine PC visit. Secondary outcomes following patient access of hearing healthcare were also considered and consisted of the percentage of patients who completed and failed the screening and who (1) scheduled, and (2) completed a diagnostic evaluation. For patients who completed the diagnostic evaluation, we also examined the percentage of those who received a hearing loss intervention plan by a hearing healthcare provider. RESULTS: All patients who had provider encouragement and support to complete the screening in the clinic completed the screening (100%) versus 26.8% with encouragement to complete the screening at home. For patients who were offered hearing screening at home, completion rates were similar regardless of provider encouragement (26.8% with encouragement versus 22.7% without encouragement); adjusted odds ratio of 1.25 (95% confidence interval 0.80-1.94). Regarding the secondary outcomes, roughly half (38.9-57.1% depending on group) of all patients who failed the hearing screening scheduled and completed a formal diagnostic evaluation. The percentage of patients who completed a diagnostic evaluation and received a hearing loss intervention plan was 35.0% to 50.0% depending on the group. Rates of a hearing loss intervention plan by audiologists ranged from 28.6% to 47.5% and were higher compared with those by otolaryngology providers, which ranged from 15.0% to 20.8% among the groups. CONCLUSIONS: The results of the pragmatic clinical trial showed that offering provider encouragement and screening facilities in the PC clinic led to a significantly higher rate of adherence with hearing screening associated with a single encounter. However, provider encouragement did not improve the significantly lower rate of adherence with home-based hearing screening.

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.

Attenuation and distortion components of age-related hearing loss: Contributions to recognizing temporal-envelope filtered speech in modulated noise.

Older adults with hearing loss may experience difficulty recognizing speech in noise due to factors related to attenuation (e.g., reduced audibility and sensation levels, SLs) and distortion (e.g., reduced temporal fine structure, TFS, processing). Furthermore, speech recognition may improve when the amplitude modulation spectrum of the speech and masker are non-overlapping. The current study investigated this by filtering the amplitude modulation spectrum into different modulation rates for speech and speech-modulated noise. The modulation depth of the noise was manipulated to vary the SL of speech glimpses. Younger adults with normal hearing and older adults with normal or impaired hearing listened to natural speech or speech vocoded to degrade TFS cues. Control groups of younger adults were tested on all conditions with spectrally shaped speech and threshold matching noise, which reduced audibility to match that of the older hearing-impaired group. All groups benefitted from increased masker modulation depth and preservation of syllabic-rate speech modulations. Older adults with hearing loss had reduced speech recognition across all conditions. This was explained by factors related to attenuation, due to reduced SLs, and distortion, due to reduced TFS processing, which resulted in poorer auditory processing of speech cues during the dips of the masker.

Talker change detection by listeners varying in age and hearing loss.

Despite a vast literature on how speech intelligibility is affected by hearing loss and advanced age, remarkably little is known about the perception of talker-related information in these populations. Here, we assessed the ability of listeners to detect whether a change in talker occurred while listening to and identifying sentence-length sequences of words. Participants were recruited in four groups that differed in their age (younger/older) and hearing status (normal/impaired). The task was conducted in quiet or in a background of same-sex two-talker speech babble. We found that age and hearing loss had detrimental effects on talker change detection, in addition to their expected effects on word recognition. We also found subtle differences in the effects of age and hearing loss for trials in which the talker changed vs trials in which the talker did not change. These findings suggest that part of the difficulty encountered by older listeners, and by listeners with hearing loss, when communicating in group situations, may be due to a reduced ability to identify and discriminate between the participants in the conversation.

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.

Afferent loss, GABA, and Central Gain in older adults: Associations with speech recognition in noise.

Deficits in auditory nerve (AN) function for older adults reduce afferent input to the cortex. The extent to which the cortex in older adults adapts to this loss of afferent input and the mechanisms underlying this adaptation are not well understood. We took a neural systems approach measuring AN and cortical evoked responses within 50 older and 27 younger human adults (59 female) to estimate central gain, or increased cortical activity despite reduced AN activity. Relative to younger adults, older adults' AN response amplitudes were smaller, but cortical responses were not. We used the relationship between AN and cortical response amplitudes in younger adults to predict cortical response amplitudes for older adults from their AN responses. Central gain in older adults was thus defined as the difference between their observed cortical responses and those predicted from the parameter estimates of younger adults. In older adults, decreased afferent input contributed to lower cortical GABA levels, greater central gain, and poorer speech recognition in noise (SIN). These effects on SIN occur in addition to, and independent from, effects attributed to elevated hearing thresholds. Our results are consistent with animal models of central gain and suggest that reduced AN afferent input in some older adults may result in changes in cortical encoding and inhibitory neurotransmission, which contribute to reduced SIN. An advancement in our understanding of the changes that occur throughout the auditory system in response to the gradual loss of input with increasing age may provide potential therapeutic targets for intervention.Significance:Age-related hearing loss is one of the most common chronic conditions of aging, yet little is known about how the cortex adapts to this loss of sensory input. We measured AN and cortical responses to the same stimulus in younger and older adults. In older adults we found hyperexcitability in cortical activity relative to concomitant declines in afferent input that are consistent with central gain Lower levels of cortical GABA, an inhibitory neurotransmitter was associated with greater central gain, which predicted poorer SIN. The results suggest that the cortex in older adults may adapt to attenuated sensory input by reducing inhibition to amplify the cortical response, but this amplification may lead to poorer SIN.

Model-Projected Cost-Effectiveness of Adult Hearing Screening in the USA.

BACKGROUND: While 60% of older adults have hearing loss (HL), the majority have never had their hearing tested. OBJECTIVE: We sought to estimate long-term clinical and economic effects of alternative adult hearing screening schedules in the USA. DESIGN: Model-based cost-effectiveness analysis simulating Current Detection (CD) and linkage of persons with HL to hearing healthcare, compared to alternative screening schedules varying by age at first screen (45 to 75 years) and screening frequency (every 1 or 5 years). Simulated persons experience yearly age- and sex-specific probabilities of acquiring HL, and subsequent hearing aid uptake (0.5-8%/year) and discontinuation (13-4%). Quality-adjusted life-years (QALYs) were estimated according to hearing level and treatment status. Costs from a health system perspective include screening ($30-120; 2020 USD), HL diagnosis ($300), and hearing aid devices ($3690 year 1, $910/subsequent year). Data sources were published estimates from NHANES and clinical trials of adult hearing screening. PARTICIPANTS: Forty-year-old persons in US primary care across their lifetime. INTERVENTION: Alternative screening schedules that increase baseline probabilities of hearing aid uptake (base-case 1.62-fold; range 1.05-2.25-fold). MAIN MEASURES: Lifetime undiscounted and discounted (3%/year) costs and QALYs and incremental cost-effectiveness ratios (ICERs). KEY RESULTS: CD resulted in 1.20 average person-years of hearing aid use compared to 1.27-1.68 with the screening schedules. Lifetime total per-person undiscounted costs were $3300 for CD and ranged from $3630 for 5-yearly screening beginning at age 75 to $6490 for yearly screening beginning at age 45. In cost-effectiveness analysis, yearly screening beginning at ages 75, 65, and 55 years had ICERs of $39,100/QALY, $48,900/QALY, and $96,900/QALY, respectively. Results were most sensitive to variations in hearing aid utility benefit and screening effectiveness. LIMITATION: Input uncertainty around screening effectiveness. CONCLUSIONS: We project that yearly hearing screening beginning at age 55+ is cost-effective by US standards.

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.

Sex-Linked Biology and Gender-Related Research Is Essential to Advancing Hearing Health.

There is robust evidence that sex (biological) and gender (behavioral/social) differences influence hearing loss risk and outcomes. These differences are noted for animals and humans-in the occurrence of hearing loss, hearing loss progression, and response to interventions. Nevertheless, many studies have not reported or disaggregated data by sex or gender. This article describes the influence of sex-linked biology (specifically sex-linked hormones) and gender on hearing and hearing interventions, including the role of sex-linked biology and gender in modifying the association between risk factors and hearing loss, and the effects of hearing loss on quality of life and functioning. Most prevalence studies indicate that hearing loss begins earlier and is more common and severe among men than women. Intrinsic sex-linked biological differences in the auditory system may account, in part, for the predominance of hearing loss in males. Sex- and gender-related differences in the effects of noise exposure or cardiovascular disease on the auditory system may help explain some of these differences in the prevalence of hearing loss. Further still, differences in hearing aid use and uptake, and the effects of hearing loss on health may also vary by sex and gender. Recognizing that sex-linked biology and gender are key determinants of hearing health, the present review concludes by emphasizing the importance of a well-developed research platform that proactively measures and assesses sex- and gender-related differences in hearing, including in understudied populations. Such research focus is necessary to advance the field of hearing science and benefit all members of society.

Investigating the characteristics of genes and variants associated with self-reported hearing difficulty in older adults in the UK Biobank.

BACKGROUND: Age-related hearing loss is a common, heterogeneous disease with a strong genetic component. More than 100 loci have been reported to be involved in human hearing impairment to date, but most of the genes underlying human adult-onset hearing loss remain unknown. Most genetic studies have focussed on very rare variants (such as family studies and patient cohort screens) or very common variants (genome-wide association studies). However, the contribution of variants present in the human population at intermediate frequencies is hard to quantify using these methods, and as a result, the landscape of variation associated with adult-onset hearing loss remains largely unknown. RESULTS: Here we present a study based on exome sequencing and self-reported hearing difficulty in the UK Biobank, a large-scale biomedical database. We have carried out variant load analyses using different minor allele frequency and impact filters, and compared the resulting gene lists to a manually curated list of nearly 700 genes known to be involved in hearing in humans and/or mice. An allele frequency cutoff of 0.1, combined with a high predicted variant impact, was found to be the most effective filter setting for our analysis. We also found that separating the participants by sex produced markedly different gene lists. The gene lists obtained were investigated using gene ontology annotation, functional prioritisation and expression analysis, and this identified good candidates for further study. CONCLUSIONS: Our results suggest that relatively common as well as rare variants with a high predicted impact contribute to age-related hearing impairment and that the genetic contributions to adult hearing difficulty may differ between the sexes. Our manually curated list of deafness genes is a useful resource for candidate gene prioritisation in hearing loss.

Sentence recognition with modulation-filtered speech segments for younger and older adults: Effects of hearing impairment and cognition.

This study investigated word recognition for sentences temporally filtered within and across acoustic-phonetic segments providing primarily vocalic or consonantal cues. Amplitude modulation was filtered at syllabic (0-8 Hz) or slow phonemic (8-16 Hz) rates. Sentence-level modulation properties were also varied by amplifying or attenuating segments. Participants were older adults with normal or impaired hearing. Older adult speech recognition was compared to groups of younger normal-hearing adults who heard speech unmodified or spectrally shaped with and without threshold matching noise that matched audibility to hearing-impaired thresholds. Participants also completed cognitive and speech recognition measures. Overall, results confirm the primary contribution of syllabic speech modulations to recognition and demonstrate the importance of these modulations across vowel and consonant segments. Group differences demonstrated a hearing loss-related impairment in processing modulation-filtered speech, particularly at 8-16 Hz. This impairment could not be fully explained by age or poorer audibility. Principal components analysis identified a single factor score that summarized speech recognition across modulation-filtered conditions; analysis of individual differences explained 81% of the variance in this summary factor among the older adults with hearing loss. These results suggest that a combination of cognitive abilities and speech glimpsing abilities contribute to speech recognition in this group.

Neural Presbyacusis in Humans Inferred from Age-Related Differences in Auditory Nerve Function and Structure.

A common complaint of older adults is difficulty understanding speech, particularly in challenging listening conditions. Accumulating evidence suggests that these difficulties may reflect a loss and/or dysfunction of auditory nerve (AN) fibers. We used a novel approach to study age-related changes in AN structure and several measures of AN function, including neural synchrony, in 58 older adults and 42 younger adults. AN activity was measured in response to an auditory click (compound action potential; CAP), presented at stimulus levels ranging from 70 to 110 dB pSPL. Poorer AN function was observed for older than younger adults across CAP measures at higher but not lower stimulus levels. Associations across metrics and stimulus levels were consistent with age-related AN disengagement and AN dyssynchrony. High-resolution T2-weighted structural imaging revealed age-related differences in the density of cranial nerve VIII, with lower density in older adults with poorer neural synchrony. Individual differences in neural synchrony were the strongest predictor of speech recognition, such that poorer synchrony predicted poorer recognition of time-compressed speech and poorer speech recognition in noise for both younger and older adults. These results have broad clinical implications and are consistent with an interpretation that age-related atrophy at the level of the AN contributes to poorer neural synchrony and may explain some of the perceptual difficulties of older adults.SIGNIFICANCE STATEMENT Differences in auditory nerve (AN) pathophysiology may contribute to the large variations in hearing and communication abilities of older adults. However, current diagnostics focus largely on the increase in detection thresholds, which is likely because of the absence of indirect measures of AN function in standard clinical test batteries. Using novel metrics of AN function, combined with estimates of AN structure and auditory function, we identified age-related differences across measures that we interpret to represent age-related reductions in AN engagement and poorer neural synchrony. Structure-function associations are consistent with an explanation of AN deficits that arise from age-related atrophy of the AN. Associations between neural synchrony and speech recognition suggest that individual and age-related deficits in neural synchrony contribute to speech recognition deficits.

Evidence for cortical adjustments to perceptual decision criteria during word recognition in noise.

Extensive increases in cingulo-opercular frontal activity are typically observed during speech recognition in noise tasks. This elevated activity has been linked to a word recognition benefit on the next trial, termed "adaptive control," but how this effect might be implemented has been unclear. The established link between perceptual decision making and cingulo-opercular function may provide an explanation for how those regions benefit subsequent word recognition. In this case, processes that support recognition such as raising or lowering the decision criteria for more accurate or faster recognition may be adjusted to optimize performance on the next trial. The current neuroimaging study tested the hypothesis that pre-stimulus cingulo-opercular activity reflects criterion adjustments that determine how much information to collect for word recognition on subsequent trials. Participants included middle-age and older adults (N = 30; age = 58.3 ± 8.8 years; m ± sd) with normal hearing or mild sensorineural hearing loss. During a sparse fMRI experiment, words were presented in multitalker babble at +3 dB or +10 dB signal-to-noise ratio (SNR), which participants were instructed to repeat aloud. Word recognition was significantly poorer with increasing participant age and lower SNR compared to higher SNR conditions. A perceptual decision-making model was used to characterize processing differences based on task response latency distributions. The model showed that significantly less sensory evidence was collected (i.e., lower criteria) for lower compared to higher SNR trials. Replicating earlier observations, pre-stimulus cingulo-opercular activity was significantly predictive of correct recognition on a subsequent trial. Individual differences showed that participants with higher criteria also benefitted the most from pre-stimulus activity. Moreover, trial-level criteria changes were significantly linked to higher versus lower pre-stimulus activity. These results suggest cingulo-opercular cortex contributes to criteria adjustments to optimize speech recognition task performance.

A pragmatic clinical trial of hearing screening in primary care clinics: cost-effectiveness of hearing screening.

BACKGROUND: Hearing loss is a high prevalence condition among older adults, is associated with higher-than-average risk for poor health outcomes and quality of life, and is a public health concern to individuals, families, communities, professionals, governments, and policy makers. Although low-cost hearing screening (HS) is widely available, most older adults are not asked about hearing during health care visits. A promising approach to addressing unmet needs in hearing health care is HS in primary care (PC) clinics; most PC providers (PCPs) do not inquire about hearing loss. However, no cost assessment of HS in community PC settings has been conducted in the United States. Thus, this study conducted a cost-effectiveness analysis of HS using results from a pragmatic clinic trial that compared three HS protocols that differed in the level of support and encouragement provided by the PC office and the PCPs to older adults during their routine visits. Two protocols included HS at home (one with PCP encouragement and one without) and one protocol included HS in the PC office. METHODS: Direct costs of the HS included costs of: (1) educational materials about hearing loss, (2) PCP educational and encouragement time, and (3) access to the HS system. Indirect costs for in-office HS included cost of space and minimal staff time. Costs were tracked and modeled for each phase of care during and following the HS, including completion of a diagnostic assessment and follow-up with the recommended treatment plan. RESULTS: The cost-effectiveness analysis showed that the average cost per patient is highest in the patient group who completed the HS during their clinic visit, but the average cost per patient who failed the HS is by far the lowest in that group, due to the higher failure rate, that is, rate of identification of patients with suspected hearing loss. Estimated benefits of HS in terms of improvements in quality of life were also far greater when patients completed the HS during their clinic visit. CONCLUSIONS: Providing HS to older adults during their PC visit is cost-effective and accrues greater estimated benefits in terms of improved quality of life. TRIAL REGISTRATION: clinicaltrials.gov (Registration Identification Number: NCT02928107).

Using Clinical Audiologic Measures to Determine Cochlear Implant Candidacy.

INTRODUCTION: Only a small percentage (6-10%) of patients who are candidates receive cochlear implants (CIs). One potential reason contributing to low usage rates may be confusion regarding which patients to refer for CI evaluation. The extent to which information provided by standard clinical audiologic assessments is sufficient for selecting appropriate CI evaluation referrals is uncertain. The objective of this study is to evaluate the capacity of standard clinical audiologic measures to differentiate CI candidates from noncandidates. METHOD: The study design is a retrospective review of a prospectively maintained CI database from a university-based tertiary medical center of 518 patients undergoing CI evaluations from 2012 to 2020. Each ear of each patient was treated as an independent value. Receiver operating characteristic (ROCs) curves were constructed using aided AzBio sentence recognition scores in quiet and aided AzBio +10 dB signal-to-noise ratio scores <60% as binary classifiers for CI candidacy. For each ROC, we examined the capacity of multiple pure-tone thresholds, pure-tone average (PTA), and CNC word recognition scores (WRSs) measured under earphones to determine CI candidacy. Area under the curve ROC (AUC-ROC) values were calculated to demonstrate the capacity of each model to differentiate CI candidates from noncandidates. RESULTS: Variables with the greatest capacity to accurately differentiate CI candidates from noncandidates using aided AzBio in quiet scores were earphone CNC WRS, earphone pure-tone threshold at 1,000 Hz, and earphone PTA (AUC-ROC values = 0.86-0.88). Using aided AzBio +10 scores as the measure for candidacy, only CNC word recognition had a fair capacity to identify candidates (AUC-ROC value = 0.73). Based on the ROCs, a 1,000 Hz pure-tone threshold >50 dB HL, PTA >57 dB HL, and a monosyllabic WRS <60% can each serve as individual indicators for referral for CI evaluations. CONCLUSION: The current study provides initial indicators for referral and a first step at developing evidence-based criteria for CI evaluation referral using standard audiologic assessments.