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

Hearing difficulty (HD) is one of the major health burdens in older adults. While aging-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 analyzed a large-scale HD genome-wide association study (GWAS; Ntotal = 501,825, 56% females) and GWAS data related to 3,935 brain imaging-derived phenotypes (IDPs) assessed in up to 33,224 individuals (52% females) using multiple magnetic resonance imaging 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 colocalization 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 IDPs in males, and 171 IDPs 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 correlations, 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 colocalization 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.

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.

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.

Estimating intracluster correlation for ordinal data.

In this paper, we consider the estimation of intracluster correlation for ordinal data. We focus on pure-tone audiometry hearing threshold data, where thresholds are measured in 5 decibel increments. We estimate the intracluster correlation for tests from iPhone-based hearing assessment applications as a measure of test/retest reliability. We present a method to estimate the intracluster correlation using mixed effects cumulative logistic and probit models, which assume the outcome data are ordinal. This contrasts with using a mixed effects linear model which assumes that the outcome data are continuous. In simulation studies, we show that using a mixed effects linear model to estimate the intracluster correlation for ordinal data results in a negative finite sample bias, while using mixed effects cumulative logistic or probit models reduces this bias. The estimated intracluster correlation for the iPhone-based hearing assessment application is higher when using the mixed effects cumulative logistic and probit models compared to using a mixed effects linear model. When data are ordinal, using mixed effects cumulative logistic or probit models reduces the bias of intracluster correlation estimates relative to using a mixed effects linear model.

Associations of Tinnitus Incidence with Use of Tumor Necrosis Factor-Alpha Inhibitors among Patients with Autoimmune Conditions.

Tumor necrosis factor-alpha (TNFα) may promote neuroinflammation prompting tinnitus. This retrospective cohort study evaluated whether anti-TNFα therapy influences incident tinnitus risk among adults with autoimmune disorders and no baseline tinnitus selected from a US electronic health records database (Eversana; 1 January 2010-27 January 2022). Patients with anti-TNFα had ≥90-day history pre-index (first autoimmune disorder diagnosis) and ≥180-day follow-up post-index. Random samples (n = 25,000) of autoimmune patients without anti-TNFα were selected for comparisons. Tinnitus incidence was compared among patients with or without anti-TNFα therapy, overall and among at-risk age groups or by anti-TNFα category. High-dimensionality propensity score (hdPS) matching was used to adjust for baseline confounders. Compared with patients with no anti-TNFα, anti-TNFα was not associated with tinnitus risk overall (hdPS-matched HR [95% CI]: 1.06 [0.85, 1.33]), or between groups stratified by age (30-50 years: 1 [0.68, 1.48]; 51-70 years: 1.18 [0.89, 1.56]) or anti-TNFα category (monoclonal antibody vs. fusion protein: 0.91 [0.59, 1.41]). Anti-TNFα was not associated with tinnitus risk among those treated for ≥6 months (hdPS-matched HR [95% CI]: 0.96 [0.69, 1.32]) or ≥12 (1.03 [0.71, 1.5]), or those with RA (1.16 [0.88, 1.53]). Thus, in this US cohort study, anti-TNFα therapy was not associated with tinnitus incidence among patients with autoimmune disorders.

Association of Plasma Metabolomic Biomarkers With Persistent Tinnitus: A Population-Based Case-Control Study.

Importance: Persistent tinnitus is common, disabling, and difficult to treat. Objective: To evaluate the association between circulating metabolites and persistent tinnitus. Design, Setting, and Participants: This was a population-based case-control study of 6477 women who were participants in the Nurses' Health Study (NHS) and NHS II with metabolomic profiles and tinnitus data. Information on tinnitus onset and frequency was collected on biennial questionnaires (2009-2017). For cases, metabolomic profiles were measured (2015-2021) in blood samples collected after the date of the participant's first report of persistent tinnitus (NHS, 1989-1999 and 2010-2012; NHS II, 1996-1999). Data analyses were performed from January 24, 2022, to January 14, 2023. Exposures: In total, 466 plasma metabolites from 488 cases of persistent tinnitus and 5989 controls were profiled using 3 complementary liquid chromatography tandem mass spectrometry approaches. Main Outcomes and Measures: Logistic regression was used to estimate odds ratios (ORs) of persistent tinnitus (per 1 SD increase in metabolite values) and 95% CIs for each individual metabolite. Metabolite set enrichment analysis was used to identify metabolite classes enriched for associations with tinnitus. Results: Of the 6477 study participants (mean [SD] age, 52 [9] years; 6477 [100%] female; 6121 [95%] White individuals) who were registered nurses, 488 reported experiencing daily persistent (≥5 minutes) tinnitus. Compared with participants with no tinnitus (5989 controls), those with persistent tinnitus were slightly older (53.0 vs 51.8 years) and more likely to be postmenopausal, using oral postmenopausal hormone therapy, and have type 2 diabetes, hypertension, and/or hearing loss at baseline. Compared with controls, homocitrulline (OR, 1.32; (95% CI, 1.16-1.50); C38:6 phosphatidylethanolamine (PE; OR, 1.24; 95% CIs, 1.12-1.38), C52:6 triglyceride (TAG; OR, 1.22; 95% CIs, 1.10-1.36), C36:4 PE (OR, 1.22; 95% CIs, 1.10-1.35), C40:6 PE (OR, 1.22; 95% CIs, 1.09-1.35), and C56:7 TAG (OR, 1.21; 95% CIs, 1.09-1.34) were positively associated, whereas α-keto-ß-methylvalerate (OR, 0.68; 95% CIs, 0.56-0.82) and levulinate (OR, 0.60; 95% CIs, 0.46-0.79) were inversely associated with persistent tinnitus. Among metabolite classes, TAGs (normalized enrichment score [NES], 2.68), PEs (NES, 2.48), and diglycerides (NES, 1.65) were positively associated, whereas phosphatidylcholine plasmalogens (NES, -1.91), lysophosphatidylcholines (NES, -2.23), and cholesteryl esters (NES,-2.31) were inversely associated with persistent tinnitus. Conclusions and Relevance: This population-based case-control study of metabolomic profiles and tinnitus identified novel plasma metabolites and metabolite classes that were significantly associated with persistent tinnitus, suggesting that metabolomic studies may help improve understanding of tinnitus pathophysiology and identify therapeutic targets for this challenging disorder.