Sex differences in the pleiotropy of hearing difficulty with imaging-derived phenotypes: a brain-wide investigation.

Hearing difficulty (HD) is a major health burden in older adults. While ageing-related changes in the peripheral auditory system play an important role, genetic variation associated with brain structure and function could also be involved in HD predisposition. We analysed a large-scale HD genome-wide association study (GWAS; ntotal = 501 825, 56% females) and GWAS data related to 3935 brain imaging-derived phenotypes (IDPs) assessed in up to 33 224 individuals (52% females) using multiple MRI modalities. To investigate HD pleiotropy with brain structure and function, we conducted genetic correlation, latent causal variable, Mendelian randomization and multivariable generalized linear regression analyses. Additionally, we performed local genetic correlation and multi-trait co-localization analyses to identify genomic regions and loci implicated in the pleiotropic mechanisms shared between HD and brain IDPs. We observed a widespread genetic correlation of HD with 120 IDPs in females, 89 in males and 171 in the sex-combined analysis. The latent causal variable analysis showed that some of these genetic correlations could be due to cause-effect relationships. For seven of them, the causal effects were also confirmed by the Mendelian randomization approach: vessel volume→HD in the sex-combined analysis; hippocampus volume→HD, cerebellum grey matter volume→HD, primary visual cortex volume→HD and HD→fluctuation amplitudes of node 46 in resting-state functional MRI dimensionality 100 in females; global mean thickness→HD and HD→mean orientation dispersion index in superior corona radiata in males. The local genetic correlation analysis identified 13 pleiotropic regions between HD and these seven IDPs. We also observed a co-localization signal for the rs13026575 variant between HD, primary visual cortex volume and SPTBN1 transcriptomic regulation in females. Brain structure and function may have a role in the sex differences in HD predisposition via possible cause-effect relationships and shared regulatory mechanisms.

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.

Hypothesis Tests for Continuous Audiometric Threshold Data.

OBJECTIVES: Hypothesis tests for hearing threshold data may be challenging due to the special structure of the response variable, which consists of the measurements from the participant's two ears at multiple frequencies. The commonly-used methods may have inflated type I error rates for the global test that examines whether exposure-hearing threshold associations exist in at least one of the frequencies. We propose using both-ear methods, including all frequencies in the same model for hypothesis testing. DESIGN: We compared the both-ear method to commonly used single-ear methods, such as the worse-ear, better-ear, left/right-ear, average-ear methods, and both-ear methods that evaluate individual audiometric frequencies in separate models, through both theoretical consideration and a simulation study. Differences between the methods were illustrated using hypothesis tests for the associations between the Dietary Approaches to Stop Hypertension adherence score and 3-year change in hearing thresholds among participants in the Conservation of Hearing Study. RESULTS: We found that (1) in the absence of ear-level confounders, the better-ear, worse-ear and left/right-ear methods have less power for frequency-specific tests and for the global test; (2) in the presence of ear-level confounders, the better-ear and worse-ear methods are invalid, and the left/right-ear and average-ear methods have less power, with the power loss in the left/right-ear much greater than the average-ear method, for frequency-specific tests and for the global test; and (3) the both-ear method with separate analyses for individual frequencies is invalid for the global test. CONCLUSIONS: For hypothesis testing to evaluate whether there are significant associations between an exposure of interest and audiometric hearing threshold measurements, the both-ear method that includes all frequencies in the same model is the recommended analytic approach.

Analytical method for detecting outlier evaluators.

BACKGROUND: Epidemiologic and medical studies often rely on evaluators to obtain measurements of exposures or outcomes for study participants, and valid estimates of associations depends on the quality of data. Even though statistical methods have been proposed to adjust for measurement errors, they often rely on unverifiable assumptions and could lead to biased estimates if those assumptions are violated. Therefore, methods for detecting potential 'outlier' evaluators are needed to improve data quality during data collection stage. METHODS: In this paper, we propose a two-stage algorithm to detect 'outlier' evaluators whose evaluation results tend to be higher or lower than their counterparts. In the first stage, evaluators' effects are obtained by fitting a regression model. In the second stage, hypothesis tests are performed to detect 'outlier' evaluators, where we consider both the power of each hypothesis test and the false discovery rate (FDR) among all tests. We conduct an extensive simulation study to evaluate the proposed method, and illustrate the method by detecting potential 'outlier' audiologists in the data collection stage for the Audiology Assessment Arm of the Conservation of Hearing Study, an epidemiologic study for examining risk factors of hearing loss in the Nurses' Health Study II. RESULTS: Our simulation study shows that our method not only can detect true 'outlier' evaluators, but also is less likely to falsely reject true 'normal' evaluators. CONCLUSIONS: Our two-stage 'outlier' detection algorithm is a flexible approach that can effectively detect 'outlier' evaluators, and thus data quality can be improved during data collection stage.

Longitudinal Study of Analgesic Use and Risk of Incident Persistent Tinnitus.

BACKGROUND: Persistent tinnitus is common, disabling, and difficult to treat. High-dose aspirin may precipitate tinnitus, but longitudinal data on typical dose aspirin and other analgesics are scarce. OBJECTIVE: To investigate independent associations of aspirin, NSAIDs, and acetaminophen and risk of incident persistent tinnitus. DESIGN: Longitudinal cohort study. SETTING: Nurses' Health Study II (1995-2017). PARTICIPANTS: A total of 69,455 women, age 31-48 years, without tinnitus at baseline. MAIN MEASURES: Information on analgesic use and tinnitus obtained by biennial questionnaires. KEY RESULTS: After 1,120,936 person-years of follow-up, 10,452 cases of incident persistent tinnitus were reported. For low-dose aspirin, the risk of developing persistent tinnitus was not elevated among frequent low-dose aspirin users. For moderate dose aspirin, frequent use was associated with higher risk of tinnitus among women aged < 60 years, but not among older women (p-interactionage = 0.003). Compared with women aged < 60 using moderate-dose aspirin < 1 day/week, the multivariable-adjusted hazard ratio (MVHR, 95% CI) among women using moderate-dose aspirin 6-7 days per week was 1.16 (1.03, 1.32). Among all women, frequent non-aspirin non-steroidal anti-inflammatory drug (NSAID) or acetaminophen use was associated with higher risk. Compared with women using NSAIDs <1 day/week, the MVHR for use 4-5days/week was 1.17 (1.08, 1.28) and for 6-7days/week was 1.07 (1.00, 1.16) (p-trend=0.001). For acetaminophen, compared with use <1 day/week, the MVHR for use 6-7days/week was 1.18 (1.07, 1.29) (p-trend=0.002). LIMITATIONS: Information on tinnitus and analgesic use was self-reported. Information on indications for analgesic use was not available. Studies in non-White women and men are needed. CONCLUSION: The risk of developing persistent tinnitus was not elevated among frequent low-dose aspirin users. Among younger women, frequent moderate-dose aspirin use was associated with higher risk. Frequent NSAID use and frequent acetaminophen use were associated with higher risk of incident persistent tinnitus among all women, and the magnitude of the risks tended to be greater with increasing frequency of use. Our results suggest analgesic users are at higher risk for developing tinnitus and may provide insight into the precipitants of this challenging disorder, but additional investigation to determine whether there is a causal association is needed.

Analytical methods for correlated data arising from multicenter hearing studies.

In epidemiological hearing studies, estimating the association between exposures and hearing loss using audiometrically-assessed hearing measurements is challenging due to the complex correlation structure in the clustered data, with clusters formed by the two ears of the same individual and the testing site and audiologist. We propose a linear mixed-effects model to take into account the multilevel correlation structures of the data. Both theoretically and in simulation studies, we compare single-ear linear regression models commonly used in published hearing loss studies with the proposed both-ears linear mixed models properly accounting for the multi-level correlations. Our findings include (1) when there are only participant-level covariates, the worse-ear linear regression models produce unbiased but typically less efficient estimators than the both-ear and average-ear approaches; (2) when there are ear-level confounders, the worse-ear method may lead to biased estimators and the average-ear method produces unbiased but typically less efficient estimators than the both-ear method; (3) the both-ear method may gain efficiency when additionally adjusting for testing sites and audiologists. As an illustrative example, we applied the single-ear and both-ear methods to assess aspirin-hearing association in the Nurses' Health Study II.

Both-Ear Method for the Analysis of Audiometric Data.

OBJECTIVE: Single-ear hearing measurements, such as better-ear, worse-ear or left/right ear, are often used as outcomes in auditory research, yet, measurements in the two ears of the same individual are often strongly but not perfectly correlated. We propose a both-ear method using the Generalized Estimating Equation approach for analysis of correlated binary ear data to evaluate determinants of ear-specific outcomes that includes information from both ears of the same individual. DESIGN: We first theoretically evaluated bias in odds ratio (OR) estimates based on worse-ear and better-ear hearing outcomes. A simulation study was conducted to compare the finite sample performances of single-ear and both-ear methods in logistic regression models. As an illustrative example, the single-ear and both-ear methods were applied to estimate the association of Dietary Approaches to Stop Hypertension adherence scores with hearing threshold elevation among 3135 women, aged 48 to 68 years, in the Nurses' Health Study II. RESULTS: Based on statistical theories, the worse-ear and better-ear methods could bias the OR estimates. The simulation results led to the same conclusion. In addition, the simulation results showed that the both-ear method had satisfactory finite sample performance and was more efficient than the single-ear method. In the illustrative example, the confidence intervals of the estimated ORs for the association of Dietary Approaches to Stop Hypertension scores and hearing threshold elevation using the both-ear method were narrower, indicating greater precision, than for those obtained using the other methods. CONCLUSIONS: The worse-ear and better-ear methods may lead to biased estimates, and the left/right ear method typically results in less-efficient estimates. In certain settings, the both-ear method using the Generalized Estimating Equation approach for analyses of audiometric data may be preferable to the single-ear methods.

Analytical methods for evaluating reliability and validity of mobile audiometry tools.

Statistical approaches that could be used as standardized methodology for evaluating reliability and validity of data obtained using remote audiometry are proposed. Using data from the Nurses' Health Study II (n = 31), the approaches to evaluate the reliability and validity of hearing threshold measurements obtained by a self-administered iPhone-based hearing assessment application (Decibel Therapeutics, Inc., Boston, MA) compared with measurements obtained by clinical (soundbooth) audiometry are described. These approaches use mixed-effects models to account for multilevel correlations, intraclass correlation coefficients (ICCs) of single and averaged measurements, and regression techniques with the generalized estimating equations (GEEs) to account for between-ear correlations. Threshold measurements obtained using the iPhone application were moderately reliable. The reliability was improved substantially by averaging repeated measurements; good reliability was achieved by averaging three repeated measurements. In the linear regression analyses that assessed validity, the range of intercepts (2.3-8.4) and range of slopes (0.4-0.7) indicated that the measurements from the application were likely biased from those obtained by clinical audiometry. When evaluating alternative hearing assessment tools, it is recommended to assess reliability through mixed-effects models and use ICCs to determine the number of repeated assessments needed to achieve satisfactory reliability. When evaluating validity, GEE methods are recommended to estimate regression coefficients.

Tinnitus and 3-Year Change in Audiometric Hearing Thresholds.

OBJECTIVES: Tinnitus and hearing loss commonly coexist, however, the temporal relation between tinnitus and hearing loss is complex and not fully understood. Our objective was to examine the longitudinal association between persistent tinnitus, bothersome tinnitus, and 3-year elevation of audiometric hearing thresholds. DESIGN: We conducted a longitudinal cohort study among 3106 women (mean age 59 years) who were participants in the Nurses' Health Study II (2012-2018). Information on tinnitus was obtained from biennial questionnaires. Longitudinal changes in air conduction thresholds (0.5 to 8 kHz) were assessed by pure-tone audiometry conducted by licensed audiologists at 19 audiology testing sites across the United States. Logistic regression was used to estimate multivariable-adjusted odds ratios (MVORs, 95% confidence interval [CI]) and evaluate the relations of persistent tinnitus (several days per week or more), bothersome tinnitus (interferes with work, sleep, or daily activities), and risk of 3-year elevation of hearing thresholds. RESULTS: Persistent tinnitus was associated with higher risk of 3-year elevation of hearing thresholds across a broad range of frequencies. Compared with women without tinnitus, the MVORs (95% CI) for ≥5-dB threshold elevation among women with persistent tinnitus were 1.01 (0.81, 1.25) at 0.5 kHz, 1.45 (1.17, 1.81) at 1 kHz, 1.25 (1.00, 1.56) at 2 kHz, 1.34 (1.07, 1.69) at 3 kHz, 1.34 (1.06, 1.70) at 4 kHz, 1.49 (1.16, 1.91) at 6 kHz, and 1.63 (1.25, 2.12) at 8 kHz. The magnitudes of the associations for ≥10-dB threshold elevation were similar. The magnitudes of the associations were substantially greater among women with bothersome tinnitus. For example, compared with women without tinnitus, the MVORs (95% CI) for a ≥5- and ≥10-dB elevation of hearing thresholds at 4 kHz were 2.97 (1.50, 5.89) and 2.79 (1.38, 5.65), respectively. The risk was elevated even among women with tinnitus who had clinically normal hearing thresholds at baseline. In analyses that examined the association of tinnitus and elevation of low-, mid- and high-frequency pure-tone average (PTA) hearing thresholds, the results were similar. Compared with women without tinnitus, the MVORs (95% CI) for ≥5-dB PTA elevation among women with persistent tinnitus were 1.29 (0.99,1.67) for LPTA(0.5,1,2 kHz); 1.44 (1.16, 1.78) for MPTA(3,4 kHz); and 1.38 (1.11, 1.71) for HPTA(6,8 kHz). For ≥10-dB elevation, the MVORs were 2.85 (1.55, 5.23), 1.52 (1.10, 2.09), and 1.41 (1.10, 1.82), respectively. CONCLUSION: Persistent tinnitus was associated with substantially higher risk of 3-year hearing threshold elevation, even among women with clinically normal baseline hearing. The magnitudes of the associations were greater among those with bothersome tinnitus. Monitoring hearing sensitivities may be indicated in patients with tinnitus, including those without audiometric evidence of hearing impairment.

Prospective Study of Dietary Patterns and Hearing Threshold Elevation.

We conducted a prospective study of dietary patterns and longitudinal change in audiometric hearing thresholds among 3,135 women (mean age = 59 years) in the Nurses' Health Study II (2012-2018). Diet adherence scores for the Dietary Approaches to Stop Hypertension (DASH) and Alternate Mediterranean (AMED) diets and the Alternate Healthy Eating Index 2010 (AHEI-2010) were calculated using validated food-frequency questionnaires. Baseline and 3-year follow-up hearing sensitivities were assessed by pure-tone audiometry at 19 US sites. We used multivariable-adjusted logistic regression models to examine independent associations between diet adherence scores and risk of ≥5 dB elevation in the pure-tone average (PTA) of low-frequency (LPTA0.5,1,2 kHz), mid-frequency (MPTA3,4 kHz), and high-frequency (HPTA6,8 kHz) hearing thresholds. Higher adherence scores were associated with lower risk of hearing loss. Compared with the lowest quintile of DASH score, the multivariable-adjusted odds ratios for mid-frequency and high-frequency threshold elevation in the highest quintile were 0.71 (95% confidence interval (CI): 0.55, 0.92; P for trend = 0.003) and 0.75 (95% CI: 0.59, 0.96; P for trend = 0.02); for AMED and AHEI scores, for mid-frequency threshold elevation, they were 0.77 (95% CI: 0.60, 0.99; P for trend = 0.02) and 0.72 (95% CI: 0.57, 0.92; P for trend = 0.002). Nonsignificant inverse associations were observed for high-frequency threshold elevation. There were no significant associations between adherence scores and low-frequency threshold elevation. Our findings indicate that eating a healthy diet might reduce the risk of acquired hearing loss.

Birth Weight and Adult-Onset Hearing Loss.

OBJECTIVES: Among low-birth-weight infants, exposure to stress or undernutrition in utero may adversely affect cochlear development. As cochlear reserve declines, the risk of hearing loss may increase with age. While low birth weight is associated with a higher risk of neonatal hearing loss, our objective was to examine whether birth weight was associated with adult-onset, self-reported hearing loss in the Nurses' Health Studies (NHS) I and II (n = 113,130). DESIGN: We used Cox proportional hazards regression to prospectively examine whether birth weight, as well as gestational age at birth, is associated with adult-onset hearing loss. Participants reported their birth weight in 1992 in NHS I and 1991 in NHS II. Mothers of NHS II participants reported gestational age at birth in a substudy (n = 28,590). The primary outcome was adult-onset, self-reported moderate or greater hearing loss, based on questionnaires administered in 2012/2016 in NHS I and 2009/2013 in NHS II. RESULTS: Our results suggested a higher risk of hearing loss among those with birth weight <5.5 lbs compared with birth weight 7 to <8.5 lbs (pooled multivariable-adjusted hazard ratio 1.14, 95% confidence interval = 1.04-1.23; p trend = 0.01). Additionally, participants with gestational age at birth ≥42 weeks had a higher risk of hearing loss, compared with gestational age 38 to <42 weeks (multivariable-adjusted hazard ratio 1.33, 95% confidence interval = 1.06-1.65). CONCLUSIONS: Birth weight <5.5 lbs was independently associated with higher risk of self-reported, adult-onset hearing loss. In addition, gestational age at birth ≥42 weeks was also associated with higher risk.

Longitudinal study of self-reported hearing loss and subjective cognitive function decline in women.

INTRODUCTION: We investigated the relation between self-reported hearing loss and risk of subjective cognitive function (SCF) decline among women. METHODS: We conducted a longitudinal study of 20,193 women in the Nurses' Health Study aged ≥66 years who reported their hearing status and had no subjective cognitive concerns in 2012. SCF scores were assessed by a 7-item questionnaire in 2012 and 2014. SCF decline was defined as a new report of at least one cognitive concern during follow-up. RESULTS: Self-reported hearing loss was associated with higher risk of SCF decline. Compared with women with no hearing loss, the multivariable-adjusted odds ratios (95% confidence interval) for incident SCF score ≥1 were 1.35 (1.25, 1.47), 1.39 (1.24, 1.56), and 1.40 (1.21, 1.75) among women with mild, moderate, and severe hearing loss, respectively. Recent progression of hearing loss was associated with even higher risk. DISCUSSION: Self-reported hearing loss was associated with higher risk of incident subjective cognitive function decline in women.

Type 2 diabetes and the risk of incident hearing loss.

AIMS/HYPOTHESIS: Type 2 diabetes mellitus has been implicated as a risk factor for hearing loss, with possible mechanisms including microvascular disease, acoustic neuropathy or oxidative stress. A few small studies have examined the longitudinal association between type 2 diabetes and hearing loss, but larger studies are needed. Our objective was to examine whether type 2 diabetes (including diabetes duration) is associated with incident hearing loss in two prospective cohorts: Nurses' Health Studies (NHS) I and II. METHODS: We conducted a longitudinal study of 139,909 women to examine the relationship between type 2 diabetes and the risk of self-reported incident hearing loss. A physician-diagnosis of diabetes was ascertained from biennial questionnaires. The primary outcome was hearing loss reported as moderate or worse in severity (categorised as a 'moderate or severe' hearing problem, or 'moderate hearing trouble or deaf') on questionnaires administered in 2012 in NHS I and 2009 or 2013 in NHS II. Cox proportional hazards regression was used to adjust for potential confounders. RESULTS: During >2.4 million person-years of follow-up, 664 cases of moderate or worse hearing loss were reported among those with type 2 diabetes and 10,022 cases among those without type 2 diabetes. Compared with women who did not have type 2 diabetes, those with type 2 diabetes were at higher risk for incident moderate or worse hearing loss (pooled multivariable-adjusted HR 1.16 [95% CI 1.07, 1.27]). Participants who had type 2 diabetes for ≥8 years had a higher risk of moderate or worse hearing loss compared with those without type 2 diabetes (pooled multivariable-adjusted HR 1.24 [95% CI 1.10, 1.40]). CONCLUSIONS/INTERPRETATION: In this large longitudinal study, type 2 diabetes was associated with a modestly higher risk of moderate or worse hearing loss. Furthermore, longer duration diabetes was associated with a higher risk of moderate or worse hearing loss.

Biomarkers of Systemic Inflammation and Risk of Incident Hearing Loss.

BACKGROUND: Chronic inflammation may lead to cochlear damage, and the only longitudinal study that examined biomarkers of systemic inflammation and risk of hearing loss found an association with a single biomarker in individuals <60 years of age. The purpose of our study was to determine whether plasma inflammatory markers are associated with incident hearing loss in two large prospective cohorts, Nurses' Health Studies (NHS) I and II. METHODS: We examined the independent associations between plasma levels of markers of systemic inflammation (C-reactive protein [CRP], interleukin-6 [IL-6], and soluble tumor necrosis factor receptor 2 [TNFR-2]) and self-reported hearing loss. The participants in NHS I (n = 6194 women) were 42 to 69 years of age at the start of the analysis in 1990, while the participants in NHS II (n = 2885 women) were 32 to 53 years in 1995. After excluding women with self-reported hearing loss before the time of blood-draw, incident cases of hearing loss were defined as those women who reported hearing loss on questionnaires administered in 2012 in NHS I and 2009 or 2013 in NHS II. The primary outcome was hearing loss that was reported as moderate or worse in severity, pooled across the NHS I and NHS II cohorts. We also examined the pooled multivariable-adjusted hazard ratios for mild or worse hearing loss. Cox proportional hazards regression was used to adjust for potential confounders. RESULTS: At baseline, women ranged from 42 to 69 years of age in NHS I and 32 to 53 years of age in NHS II. Among the NHS I and II women with measured plasma CRP, there were 628 incident cases of moderate or worse hearing loss during 100,277 person-years of follow-up. There was no significant association between the plasma levels of any of the three inflammatory markers and incident moderate or worse hearing loss (multivariable-adjusted pooled p trend for CRP = 0.33; p trend IL-6 = 0.54; p trend TNFR-2 = 0.70). There was also no significant relation between inflammatory marker levels and mild or worse hearing loss. While there was no significant effect modification by age for CRP or IL-6 in NHS I, there was a statistically significant higher risk of moderate or worse hearing loss (p interaction = 0.02) as well as mild or worse hearing loss (p interaction = 0.004) in women ≥60 years of age who had higher plasma TNFR-2 levels. CONCLUSIONS: Overall, there was no significant association between plasma markers of inflammation and risk of hearing loss.

Longitudinal study of hearing loss and subjective cognitive function decline in men.

INTRODUCTION: We examined the relation between self-reported hearing loss, hearing aid use, and risk of subjective cognitive function (SCF) decline. METHODS: We conducted an 8-year (2008-2016) longitudinal study of 10,107 men aged ≥62 years who reported their hearing status in 2006 and had no subjective cognitive concerns in 2008. Change in SCF scores was assessed by a 6-item questionnaire, and subjective decline was defined as new report of at least one SCF concern during follow-up. RESULTS: Hearing loss was associated with higher risk of SCF decline. Compared with no hearing loss, the multivariable-adjusted relative risk (95% CI) of incident SCF decline was 1.30 (1.18, 1.42), 1.42 (1.26, 1.61), and 1.54 (1.22, 1.96) among men with mild, moderate, and severe hearing loss (no hearing aids), respectively (P-trend < .001). Among men with severe hearing loss who used hearing aids, the multivariable-adjusted relative risk (95% CI) was 1.37 (1.18, 1.60). DISCUSSION: Hearing loss was associated with substantially higher risk of subsequent subjective cognitive decline in men.

Adherence to Healthful Dietary Patterns Is Associated with Lower Risk of Hearing Loss in Women.

Background: Specific nutrients have been associated with hearing status, but associations between healthful dietary patterns and risk of hearing loss have not been prospectively evaluated. Objective: We sought to prospectively examine the relations between adherence to the Alternate Mediterranean diet (AMED), the Dietary Approaches to Stop Hypertension (DASH), and the Alternative Healthy Eating Index-2010 (AHEI-2010), and risk of hearing loss. Methods: We conducted a longitudinal cohort study (1991-2013) of 81,818 women in the Nurses' Health Study II, aged 27-44 y at baseline. We assessed diet every 4 y with the use of food frequency questionnaires and calculated AMED, DASH, and AHEI-2010 adherence scores. Baseline and updated information from validated biennial questionnaires was used in Cox proportional hazards regression models to examine independent associations between adherence scores and risk of self-reported moderate or worse hearing loss. Results: During >1 million person-years of follow-up, 2306 cases of moderate or worse hearing loss were reported. Higher cumulative average AMED and DASH scores were significantly inversely associated with risk of hearing loss. For women with scores in the highest compared with the lowest quintile, the multivariable-adjusted relative risks (MVRRs) of hearing loss were 0.70 (95% CI: 0.60, 0.82) (P-trend <0.001) for AMED and 0.71 (95% CI: 0.61, 0.83) (P-trend <0.001) for DASH. Higher recent AHEI-2010 score was also associated with lower risk [MVRR = 0.79 (95% CI: 0.69, 0.91); P-trend <0.001]. Among participants with additional hearing-related information (n = 33,102), higher cumulative average adherence scores for all 3 dietary patterns were associated with lower risk; the MVRR was 0.63 (95% CI: 0.49, 0.81) for AMED, 0.64 (95% CI: 0.50, 0.83) for DASH, and 0.71 (95% CI: 0.56, 0.89) for AHEI-2010. Conclusion: Adherence to healthful dietary patterns is associated with lower risk of hearing loss in women. Consuming a healthy diet may be helpful in reducing the risk of acquired hearing loss.

Skin Pigmentation and Risk of Hearing Loss in Women.

Black individuals have a lower risk of hearing loss than do whites, possibly because of differences in cochlear melanocytes. Previous studies have suggested that darker-skinned individuals tend to have more inner ear melanin, and cochlear melanocytes are important in generating the endocochlear potential. We investigated the relationship between self-reported hearing loss and skin pigmentation by using hair color, skin tanning ability, and skin reaction to prolonged sun exposure as surrogate measures of pigmentation among 49,323 white women in the Nurses' Health Study. Cox proportional hazards regression models were used to adjust for potential confounders. During 1,190,170 person-years of follow-up (1982-2012), there was no association between risk of hearing loss and hair color (for black hair vs. red or blonde hair, multivariable-adjusted relative risk (RR) = 0.99, 95% confidence interval (CI): 0.90, 1.09), skin tanning ability (for dark tan vs. no tan, multivariable-adjusted RR = 0.98, 95% CI: 0.92, 1.05), skin reaction to prolonged sun exposure (for painful burn with blisters vs. practically no reaction, multivariable-adjusted RR = 1.01, 95% CI: 0.93, 1.08), or Fitzpatrick skin phototype (for type IV vs. type I, multivariable-adjusted RR = 0.99, 95% CI: 0.92, 1.05). In our cohort of white women, surrogates for skin pigmentation were not associated with risk of hearing loss.

Duration of Analgesic Use and Risk of Hearing Loss in Women.

Aspirin, nonsteroidal antiinflammatory drugs (NSAID), and acetaminophen are commonly used. Frequent use of analgesics has been associated with a higher risk of hearing loss. However, the association between duration of analgesic use and the risk of hearing loss is unclear. We investigated the relationship between duration of analgesic use and self-reported hearing loss among 55,850 women in the Nurses' Health Study. Cox proportional hazards regression was used to adjust for potential confounders. During 873,376 person-years of follow-up (1990-2012), longer durations of NSAID use (for >6 years of use compared with <1 year, multivariable-adjusted relative risk = 1.10, 95% confidence interval: 1.06, 1.15; P for trend < 0.001) and acetaminophen use (for >6 years of use compared with <1 year, multivariable-adjusted relative risk = 1.09, 95% confidence interval: 1.04, 1.14; P for trend < 0.001) were associated with higher risks of hearing loss. Duration of aspirin use was not associated with hearing loss (for >6 years of use compared with <1 year, multivariable-adjusted relative risk = 1.01, 95% confidence interval: 0.97, 1.05; P for trend = 0.35). In this cohort of women, longer durations of NSAID and acetaminophen use were associated with slightly higher risks of hearing loss, but duration of aspirin use was not. Considering the high prevalence of analgesic use, this may be an important modifiable contributor to hearing loss.

Prospective Study of Gastroesophageal Reflux, Use of Proton Pump Inhibitors and H2-Receptor Antagonists, and Risk of Hearing Loss.

OBJECTIVES: Gastroesophageal reflux disease (GERD) is common and often treated with proton pump inhibitors (PPIs) or H2-receptor antagonists (H2-RAs). GERD has been associated with exposure of the middle ear to gastric contents, which could cause hearing loss. Treatment of GERD with PPIs and H2-RAs may decrease exposure of the middle ear to gastric acid and decrease the risk of hearing loss. We prospectively investigated the relation between GERD, use of PPIs and H2-RAs, and the risk of hearing loss in 54,883 women in Nurses' Health Study II. DESIGN: Eligible participants, aged 41 to 58 years in 2005, provided information on medication use and GERD symptoms in 2005, answered the question on hearing loss in 2009 or in 2013, and did not report hearing loss starting before the date of onset of GERD symptoms or medication use. The primary outcome was self-reported hearing loss. Cox proportional hazards regression was used to adjust for potential confounders. RESULTS: During 361,872 person-years of follow-up, 9842 new cases of hearing loss were reported. Compared with no GERD symptoms, higher frequency of GERD symptoms was associated with higher risk of hearing loss (multivariable adjusted relative risks: <1 time/month 1.04 [0.97, 1.11], several times/week 1.17 [1.09, 1.25], daily 1.33 [1.19, 1.49]; p value for trend <0.001). After accounting for GERD symptoms, neither PPI nor H2-RA use was associated with the risk of hearing loss. CONCLUSIONS: GERD symptoms are associated with higher risk of hearing loss in women, but use of PPIs and H2-RAs are not independently associated with the risk.