Epidemiology and risk factors of hearing loss in thyroid eye disease in the United States: A retrospective study of MarketScan® data

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Brant, Vinaya Manchaiah, Junjie Ma, Deepika Chauhan, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8801141/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Background Large-scale studies characterizing hearing loss among patients with Graves disease (GD) and thyroid eye disease (TED) in the United States are lacking. This study aimed to quantify hearing loss incidence, prevalence, and risk in this population. Methods Retrospective study of Merative™ MarketScan® Research Databases (2014–2019) data including individuals aged ≥ 18 years with TED (≥ 1 GD diagnosis and ≥ 1 eye sign/symptom within 12 months), GD (≥ 2 outpatient [≥ 30 days apart]/≥1 inpatient GD diagnoses), or in the general population (GP). Index date was the latter of first GD diagnosis or eye sign/symptom for the TED cohort, the first GD diagnosis for the GD cohort, and the first eligible claim for the GP (baseline: 12 months pre-index; follow-up: from index until hearing loss, disenrollment, death, or data end). Cox models estimated unadjusted/adjusted hazard ratios (HRs) controlling for patient characteristics; time-to-event outcomes were described using Kaplan-Meier methods. Outcomes included incidence, cumulative incidence, prevalence, and HR for hearing loss (identified by ICD-10-CM codes as a composite of conductive hearing loss, sensorineural hearing loss [SNHL], mixed conductive and SNHL, age-related hearing loss). Outcomes were standardized to the 2020 US population by age and sex. Results Overall, 20,493,563 (TED: 38,723; GD: 171,831; GP: 20,283,009) patients were included. Measures of hearing loss were highest in TED (incidence: 142.2 per 10,000 person-years; cumulative incidence: 2.8%; prevalence: 4.6%) versus GD (92.0; 2.0%; 3.0%) and GP (67.6; 1.6%; 2.2%). SNHL was the most frequent subtype. TED showed increased unadjusted risk versus GP (HR 2.6; 95% confidence interval [CI], 2.5–2.8), persisting after adjustment (HR 1.6; 95% CI, 1.5–1.7) with a 60% higher risk of hearing loss. Cumulative incidence increased with age, with patients with TED having higher rates than those with GD or in the GP (18–35 years: 0.8%, 0.4%, and 0.3% for TED, GD, and GP; ≥86 years: 11.5%, 8.9%, and 7.3%). Cumulative incidence was higher among males than females (TED: 4.3% vs. 3.0%; GD: 2.5% vs. 2.0%; GP: 1.6% vs. 1.3%). Conclusions TED and GD are independently associated with high rates of hearing loss diagnosis, supporting their recognition as systemic autoimmune diseases with auditory implications. Thyroid eye disease Graves’ disease hearing loss sensorineural hearing loss Figures Figure 1 Figure 2 Figure 3 BACKGROUND Graves’ disease (GD) is a chronic autoimmune disorder of the thyroid gland characterized by excessive thyroid hormone production and release. 1 Beyond its endocrine manifestations, GD is associated with autoimmune conditions such as systemic rheumatoid arthritis, lupus erythematosus, and type 1 diabetes mellitus. 2 , 3 It may also impact non-thyroidal organ systems, notably the eyes and ears. 4 , 5 Thyroid eye disease (TED), also known as Graves’ orbitopathy or thyroid-associated ophthalmopathy, is the primary extrathyroidal manifestation observed in GD. 6 Typically characterized by inflammation/edema and expansion of extraocular muscles causing proptosis, diplopia and pain, 6 TED has recently been associated with hearing dysfunction. 4 , 7 – 9 In a large population-based study, adjusted analyses showed that sudden sensorineural hearing loss (SNHL) had 54% higher odds in individuals with hypothyroidism and 41% higher odds in those with hyperthyroidism, compared with matched controls without thyroid disease. 10 A cross-sectional, case-control study found worse high-frequency hearing ability in patients with newly diagnosed GD, compared with healthy controls. 7 Recent analyses have also documented audiometric abnormalities in GD and TED, irrespective of medication use, with decreased high-frequency sensitivity and mild-to-moderate SNHL reported in up to 23.5% of patients, further strengthening the evidence that thyroid autoimmunity affects the auditory system. 4 Although the exact pathophysiology is not fully understood, several mechanisms have been proposed to explain the link between thyroid autoimmunity and auditory dysfunction. Autoimmune-mediated inflammation may cause damage to cochlear hair cells or interfere with synaptic transmission, leading to SNHL. 11 Systemic inflammatory vascular changes could similarly compromise cochlear perfusion, resulting in ischemic injury and impaired auditory function. 11 Ototoxicity from thyroid medications has also been proposed as a contributing factor. 12 Regardless of the underlying pathophysiology, hearing impairment carries a substantial personal and societal burden. It limits communication and social interaction, adversely affecting relationships, occupational performance, and mental health, with established links to depression, cognitive impairment, and poor quality of life. 13 – 15 In the context of GD and TED, recognition of hearing loss is particularly important, as it can potentially exacerbate the psychosocial burden already associated with these disorders. Several comorbidities commonly associated with GD and TED contribute to the risk of hearing dysfunction in these conditions. Type 2 diabetes can cause auditory impairment through microvascular and neuropathic changes affecting cochlear and auditory nerve function. 16 Hypertension can damage cochlear microvasculature, particularly the stria vascularis, impairing perfusion. 17 Additionally, male sex at birth has been consistently associated with a high prevalence of hearing impairment, owing to lifetime occupational noise exposure and the absence of estrogen’s protective effects. 18 , 19 These overlapping metabolic, vascular, and epidemiological factors may act synergistically in GD and TED, heightening the risk of auditory dysfunction and potentially contributing to irreversible impairment if unrecognized. Despite emerging evidence showing higher rates of sudden SNHL in hypothyroidism and hyperthyroidism, important gaps in knowledge remain. Existing studies are small, cross-sectional, or descriptive, which limits the ability to draw causal inferences. Few investigations differentiate between types of hearing impairment, such as sensorineural versus conductive hearing loss, thereby constraining mechanistic insights. In addition, research on the effects of thyroid-related treatments, including antithyroid drugs, corticosteroids, and teprotumumab, on auditory outcomes is lacking. There remains a clear need for large-scale studies to characterize hearing loss among patients with GD and TED. This study aimed to quantify the real-world cumulative incidence, incidence rates, and prevalence of hearing loss in the United States (US) using a large administrative claims database. A further aim was to evaluate longitudinal risk and predictors of hearing loss, comparing outcomes in patients with either condition to those in the general population (GP). METHODS Data source and design This was a retrospective, multi-cohort study of longitudinal medical and pharmacy de-identified patient data from the Merative™ MarketScan® Research Claims Database (January 1, 2014–December 31, 2019). Patients were categorized into three cohorts. The TED cohort included patients with ≥ 1 claim for GD and an eye manifestation (i.e., diplopia, lid retraction, strabismus, exophthalmos) within a 12-month interval (index date: latter observed claim of the first code for GD or eye manifestation). The GD cohort included patients with ≥ 2 outpatient GD diagnoses > 30 days apart, or ≥ 1 inpatient GD diagnosis without qualifying TED features (index date: first observed claim with a GD diagnosis code). Individuals with ≥ 1 claim who did not meet criteria for GD or TED were included in the GP cohort (index date: first eligible medical claim). Eligible patients were required to be ≥ 18 years old with continuous health plan enrollment for ≥ 12 months before and ≥ 6 months after the index date, allowing for gaps of < 45 days. The baseline period was the 12 months prior to the index date, and the follow-up period extended from index until the earliest of occurrence of hearing loss, health plan disenrollment, death, or end of data availability. Patients with a diagnosis of hearing loss during the baseline period were excluded from incidence analyses (Fig. 1 ). Outcome measures The primary outcome was hearing loss, defined as a composite of conductive hearing loss, SNHL, mixed conductive and SNHL, age-related hearing loss, and other hearing loss (i.e., sudden hearing loss, unspecified hearing loss, other specified hearing loss). SNHL was evaluated as a secondary outcome. For each cohort, baseline demographic and clinical characteristics were estimated, with concurrent conditions defined as ≥ 2 outpatient or ≥ 1 inpatient code of interest. We also estimated hearing loss cumulative incidence, incidence rates per 10,000 person-years, and prevalence; each measure was standardized to the 2020 US standard population by age and sex at birth (sex) using the most recent census distribution available to enhance comparability across cohorts and account for differences versus the US population. Statistical analysis Baseline demographic and clinical characteristics were summarized descriptively, using means and medians with standard deviation (SD) for continuous variables and frequency counts with percentages for categorical variables. Standardized cumulative incidence (%), incidence rates (per 10,000 person-years), and prevalence (%) of hearing loss were descriptively reported for each cohort (TED, GD, and GP). Additional subgroup analyses were conducted to summarize cumulative incidence (%), incidence rates (per 10,000 person-years), and prevalence (%) of hearing loss by age and sex. Missing data were handled by excluding unknown values for continuous variables, whereas categorical variables comprised an ‘unknown’ category. Cox proportional hazards models were used to estimate the risk and predictors of hearing loss, adjusting for age, sex, geographic region, concurrent conditions, and use of ototoxic medications including salicylates, macrolide antibiotics, and aminoglycosides. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were reported, with an HR ≥ 1.3 indicating clinically meaningful predictors (i.e., increasing the relative risk of an event by ≥ 30%). 20 Kaplan-Meier methods were used to estimate time to hearing loss; patients were censored at their last recorded observation or at the end of the study period. The evaluation of time-to-event risk and predictors was replicated for the SNHL subcategory. All analyses were performed using Spark SQL on Databricks and SAS 9.4. This study was deemed exempt by the Western Institutional Review Board-Copernicus Group (WCG® IRB) under 45 CFR § 46.104(d)(4) due to the retrospective study design, anonymized nature of the data analyzed, and low risk of confidentiality breach. This retrospective study was conducted in accordance with the Declaration of Helsinki and applicable regulatory requirements. As it involved analysis of de-identified data, no direct patient contact occurred and informed consent was not required. RESULTS Baseline patient characteristics A total of 20,493,563 (TED: 38,723; GD: 171,831; GP: 20,283,009) patients met criteria for inclusion. Patient demographics and clinical characteristics by cohort are summarized in Table 1 . Mean (SD) age was 55.2 (15.5) years in TED, 52.8 (15.7) in GD, and 47.4 (16.8) in GP. Females accounted for 79.8%, 78.2%, and 53.3% in TED, GD, and the GP, respectively. Commercial insurance was the predominant type of coverage across all cohorts, with rates of 72.6% in TED, 77.9% in GD, and 83.9% in GP. Table 1 Baseline patient demographics and clinical characteristics TED N = 38723 GD N = 171831 GP N = 20283009 Demographics Age (years), mean ± SD [median] 55.2 ± 15.5 [56.0] 52.8 ± 15.7 [53.0] 47.4 ± 16.8 [48.0] Age group, n (%) 18–35 4394 (11.3) 25253 (14.7) 5436970 (26.8) 36–45 5432 (14.0) 28669 (16.7) 3632842 (17.9) 46–55 9061 (23.4) 41942 (24.4) 4429317 (21.8) 56–65 11459 (29.6) 46192 (26.9) 4283453 (21.1) 66–75 4292 (11.1) 15017 (8.7) 1420819 (7.0) 76–85 2887 (7.5) 10053 (5.9) 766465 (3.8) ≥ 86 1198 (3.1) 4705 (2.7) 313143 (1.5) Sex, n (%) Male 7807 (20.2) 37391 (21.8) 9468582 (46.7) Female 30916 (79.8) 134440 (78.2) 10814427 (53.3) Geographic region 1 , n (%) South 12165 (39.5) 57802 (40.2) 6495435 (36.3) Northeast 7887 (25.6) 32581 (22.6) 3920869 (21.9) North Central 6192 (20.1) 29353 (20.4) 3975533 (22.2) West 4529 (14.7) 24181 (16.8) 3488840 (19.5) Health plan, n (%) Commercial only 28123 (72.6) 133830 (77.9) 17027411 (83.9) Medicare only 5354 (13.8) 19625 (11.4) 1619437 (8.0) Both Commercial & Medicare 5246 (13.5) 18376 (10.7) 1636161 (8.1) Clinical characteristics CCI, mean ± SD [median] 0.6 (1.3) 0.4 (1.1) 0.2 (0.7) Concurrent conditions 2 , n (%) Hypertension 17733 (45.8) 68727 (40.0) 4443305 (21.9) Dyslipidemia/Hyperlipidemia 16642 (43.0) 61657 (35.9) 4059124 (20.0) Obesity 7756 (20.0) 25170 (14.6) 909438 (4.5) Mental health disorders 3 7513 (19.4) 22649 (13.2) 1024304 (5.1) Type 2 diabetes 6942 (17.9) 27506 (16.0) 1718302 (8.5) Vitamin D deficiency 6895 (17.8) 21906 (12.7) 666668 (3.3) Ischemic heart disease 3880 (10.0) 12959 (7.5) 803268 (4.0) Smoking or nicotine dependency 4127 (10.7) 13079 (7.6) 553080 (2.7) Dry eye 3515 (9.1) 4452 (2.6) 203842 (1.0) COPD 3101 (8.0) 10610 (6.2) 487683 (2.4) CKD without dialysis 3139 (8.1) 10020 (5.8) 456961 (2.3) Hyperglycemia 1473 (3.8) 3398 (2.0) 6353 (0.0) Glaucoma 1241 (3.2) 3196 (1.9) 262912 (1.3) Muscle spasms (symptomatic presentation) 1266 (3.3) 3964 (2.3) 233024 (1.1) Rheumatoid arthritis 1088 (2.8) 3084 (1.8) 165178 (0.8) Type 1 diabetes 1053 (2.7) 4153 (2.4) 188731 (0.9) Non-AD dementia 577 (1.5) 1793 (1.0) 70083 (0.3) Ocular hypertension 451 (1.2) 824 (0.5) 52319 (0.3) Systemic lupus erythematosus 424 (1.1) 905 (0.5) 40068 (0.2) Psoriasis 436 (1.1) 1306 (0.8) 102544 (0.5) Medication use 2 , n (%) NSAIDs 15178 (39.2) 55220 (32.1) 4054589 (20.0) Opioids 10321 (26.7) 34056 (19.8) 2095105 (10.3) Macrolide antibiotics 8643 (22.3) 29672 (17.3) 2054492 (10.1) Aminoglycosides 3476 (9.0) 6306 (3.7) 442902 (2.2) Loop diuretics 2659 (6.9) 9188 (5.3) 412419 (2.0) Erythromycin 1130 (2.9) 1669 (1.0) 123463 (0.6) Salicylates 955 (2.5) 2599 (1.5) 154269 (0.8) Quinine based medications 610 (1.6) 1482 (0.9) 80638 (0.4) Chemotherapy drugs 564 (1.5) 1792 (1.0) 106031 (0.5) Follow-up period Duration of follow-up period (years), median [IQR] 1.9 (1.0, 3.2) 2.0 (1.0, 3.5) 2.0 (0.9, 4.0) Table summarizing baseline patient demographics, clinical characteristics, and study period across study cohorts 1 Proportions were calculated among patients with data availability. 2 Categories are not mutually exclusive. 3 Includes anxiety, major depressive disorder, stress, dysthymic disorder, panic disorder, bipolar, mood disorder, phobia, nervousness, dementia, and manic disorder. AD, Alzheimer’s disease; CCI, Charlson Comorbidity Index; CKD, chronic kidney disease, COPD, chronic obstructive pulmonary disease; GD, Graves’ disease; GP, general population; IQR, interquartile range; N, number of patients; NSAID, nonsteroidal anti-inflammatory drug; SD, standard deviation; TED, thyroid eye disease. [Please insert Table 1 here] Common baseline concurrent conditions included hypertension (TED: 45.8%; GD: 40.0%; GP: 21.9%), hyperlipidemia (TED: 43.0%; GD: 35.9%; GP: 20.0%), obesity (TED: 20.0%, GD: 14.6%; GP: 4.5%), emotional stress (TED: 19.4%; GD: 13.2%; GP: 5.1%), and vitamin D deficiency (TED: 17.8%; GD: 12.7%; GP: 3.3%). In terms of baseline ototoxic medication use, nonsteroidal anti-inflammatory drugs (NSAIDs) were used by 39.2% of patients in the TED cohort, and by 32.1% and 20.0% in the GD and GP cohorts, respectively. Opioid use was 26.7%, 19.8%, and 10.3%, in TED, GD and GP, and macrolide antibiotic use was 22.3%, 17.3%, and 10.1%. Hearing loss incidence and prevalence After standardization by age and sex, incidence of hearing loss was 142.2 per 10,000 person-years in TED, 92.0 per 10,000 person-years in GD, and 67.6 per 10,000 person-years in GP (Table 2 ). Cumulative incidence for TED, GD, and GP was 2.8%, 2.0% and 1.6%, respectively; prevalence was 4.6%, 3.0% and 2.2%. Among subtypes of hearing loss, SNHL had the greatest cumulative incidence across all 3 cohorts, with 2.1% in TED, 1.4% in GD, and 1.1% in GP, with other types including conductive (0.4%, 0.2%, 0.1%), mixed conductive-sensorineural (0.2%, 0.2%, 0.1%), and other hearing loss (0.9%, 0.7%, 0.5%) ( Additiona Table 1 ). Table 2 Age- and gender-standardized cumulative incidence, incidence rates, and prevalence of hearing loss TED N = 38723 GD N = 171831 GP N = 20283009 Cumulative incidence, % (95% CI) 2.8% (2.6%, 3.0%) 2.0% (1.9%, 2.0%) 1.6% (1.6%, 1.6%) Incidence, per 10000 person-years (95% CI) 142.2 (132.3,152.1) 92.0 (88.2, 95.7) 67.6 (67.3, 67.9) Prevalence, % (95% CI) 4.6% (4.4%, 4.8%) 3.0% (2.9%, 3%) 2.2% (2.2%, 2.2%) Table summarizing age- and gender-standardized cumulative incidence, incidence rates, and prevalence of hearing loss (composite outcome) across study cohorts. CI, confidence interval; GD: Graves’ disease; GP, general population; N, number of patients; TED, thyroid eye disease. [Please insert Table 2 here] Subgroup analyses Cumulative incidence of hearing loss increased with age in all cohorts, from 0.8%, 0.4%, and 0.3% at 18–35 years to 11.5%, 8.9%, and 7.3% at ≥ 86 years in TED, GD, and GP, respectively (Table 3 ). When stratified by sex, among males the cumulative incidence of hearing loss was 4.3% in TED, 2.5% in GD, and 1.6% in GP, compared with 3.0%, 2.0%, and 1.3% in females (Table 3 ). Table 3 Cumulative incidence, incidence, and prevalence of hearing loss stratified by age and sex\ TED N = 38723 GD N = 171831 GP N = 20283009 Age groups Cumulative incidence, % (95% CI) 18–35 years 0.8% (0.6%, 1.1%) 0.4% (0.3%, 0.5%) 0.3% (0.3%, 0.3%) 36–45 years 1.4% (1.1%, 1.8%) 0.8% (0.7%, 0.9%) 0.6% (0.6%, 0.6%) 46–55 years 2.1% (1.8%, 2.4%) 1.4% (1.3%, 1.5%) 1.2% (1.2%, 1.2%) 56–65 years 2.9% (2.6%, 3.2%) 2.2% (2.1%, 2.3%) 1.9% (1.9%, 1.9%) 66–75 years 5.7% (5.0%, 6.4%) 4.2% (3.8%, 4.5%) 3.6% (3.6%, 3.6%) 76–85 years 9.0% (8.0%, 10.1%) 6.5% (6.0%, 7.0%) 5.7% (5.7%, 5.8%) ≥ 86 years 11.5% (9.6%, 13.4%) 8.9% (8.1%, 9.8%) 7.3% (7.2%, 7.4%) Incidence, per 10000 person-years (95% CI) 18–35 years 39.9 (39.9, 39.9) 19.4 (19.4, 19.4) 13.0 (13.0, 13.0) 36–45 years 64.4 (44.8, 84.0) 32.4 (32.4, 32.4) 23.1 (23.1, 23.1) 46–55 years 91.6 (91.6, 91.6) 55.6 (55.6, 55.6) 42.2 (42.2, 42.2) 56–65 years 137.9 (118.3, 157.5) 95.7 (95.7, 95.7) 73.4 (73.4, 73.4) 66–75 years 286.8 (252.9, 320.8) 195.8 (176.2, 215.4) 158.0 (158.0, 158.0) 76–85 years 480.6 (421.8, 539.4) 315.7 (288.0, 343.4) 241.7 (241.7, 241.7) ≥ 86 years 659.5 (546.9, 772.1) 493.1 (445.0, 541.1) 348.2 (348.2, 348.2) Prevalence, % (95% CI) 18–35 years 1.3% (1.0%, 1.7%) 0.7% (0.6%, 0.8%) 0.4% (0.4%, 0.4%) 36–45 years 2.3% (1.9%, 2.7%) 1.1% (1.0%, 1.3%) 0.8% (0.8%, 0.8%) 46–55 years 3.3% (2.9%, 3.7%) 2.0% (1.8%, 2.1%) 1.5% (1.5%, 1.5%) 56–65 years 4.9% (4.5%, 5.3%) 3.2% (3.1%, 3.4%) 2.5% (2.5%, 2.5%) 66–75 years 9.5% (8.6%, 10.3%) 6.4% (6.0%, 6.8%) 5.1% (5.1%, 5.2%) 76–85 years 14.0% (12.7%, 15.2%) 9.8% (9.3%, 10.4%) 8.3% (8.2%, 8.3%) ≥ 86 years 17.7% (15.5%, 19.9%) 13.5% (12.5%, 14.5%) 10.9% (10.7%, 11.0%) Sex Cumulative incidence, % (95% CI) Male 4.3% (3.8%, 4.7%) 2.5% (2.4%, 2.7%) 1.6% (1.6%, 1.6%) Female 3.0% (2.8%, 3.2%) 2.0% (1.9%, 2.0%) 1.3% (1.3%, 1.3%) Incidence, per 10000 person-years (95% CI) Male 204.7 (185.1, 224.3) 111.4 (111.4, 111.4) 61.8 (61.8, 61.8) Female 139.6 (139.6, 139.6) 84.2 (84.2, 84.2) 50.1 (50.1, 50.1) Prevalence, % (95% CI) Male 7.2% (6.7%, 7.8%) 4.0% (3.8%, 4.1%) 2.1% (2.1%, 2.1%) Female 4.8% (4.6%, 5.1%) 2.9% (2.8%, 3.0%) 1.8% (1.8%, 1.8%) Table summarizing the cumulative incidence, incidence, and prevalence of hearing loss (composite outcome) stratified by age groups and sex across study cohorts. CI, confidence interval; GD: Graves’ disease; GP, general population; N, number of patients; TED, thyroid eye disease. [Please insert Table 3 here] Risk and predictors of hearing loss In unadjusted analyses, the HR for hearing loss was 2.6 (95% CI, 2.5–2.8) in the TED cohort and 1.6 (95% CI, 1.5–1.6) in the GD cohort, relative to the GP. After adjustment for patient characteristics, the HR remained elevated at 1.6 (95% CI, 1.5–1.7) in TED and 1.2 (95% CI, 1.2–1.3) in GD, corresponding to a 60% and 20%, respectively, higher risk of hearing loss. Independent key predictors of hearing loss with HRs ≥ 1.3 included advanced age, male sex, selected concurrent conditions such as tinnitus, dry eye, and muscle spasms, as well as use of ototoxic medications including aminoglycosides and macrolide antibiotics (Fig. 2 ). Kaplan-Meier curves demonstrated a progressive increase in risk of hearing loss over time across all cohorts, with the TED and GD curves consistently above that of the GP cohort (Fig. 3 ). In subgroup analyses, the unadjusted HR for SNHL was 2.9 (95% CI, 2.7–3.1) in the TED cohort and 1.6 (95% CI, 1.5–1.7) in the GD cohort, relative to the GP cohort. After adjustment, the HR was 1.7 (95% CI, 1.6–1.8) in TED and 1.2 (95% CI, 1.2–1.3) in GD, corresponding to a 70% and 20%, respectively, higher risk of SNHL versus the GP cohort. Key predictors of SNHL (HR ≥ 1.3) mirrored those identified in the main analysis of overall hearing loss and included advanced age, male sex, concurrent conditions such as tinnitus, dry eye, and muscle spasms, as well as use of ototoxic medications including aminoglycosides and macrolide antibiotics. Additional predictors unique to SNHL were ocular hypertension and psoriasis ( Additional Fig. 1 ). Kaplan-Meier curves showed a progressive increase in SNHL risk over time across all cohorts, with the TED and GD curves being consistently higher than those of the GP ( Additional Fig. 2 ). DISCUSSION The results of this large-scale, real-world study highlight a consistent association between thyroid autoimmunity and auditory dysfunction. Across all outcome metrics, including incidence, cumulative incidence, and prevalence, patients with TED consistently showed the greatest burden of hearing loss compared to those with GD and the GP. In unadjusted analyses, patients with TED had more than twice the risk of hearing loss relative to the GP (HR 2.6; 95% CI, 2.5–2.8). This association remained significant after adjustment for age, sex, concurrent conditions, and ototoxic medication use, with a 60% higher risk observed among patients with TED (HR 1.6; 95% CI, 1.5–1.7). Patients with GD also demonstrated elevated, though comparatively lower than the TED population, risk (adjusted HR 1.2; 95% CI, 1.2–1.3) for hearing loss. SNHL was the most frequent subtype and the primary contributor to overall incidence and prevalence. Subgroup analyses confirmed the influence of age, with increasing hearing loss prevalence across all cohorts. Notably, even among young adults aged 18–35 years, a group generally considered at very low risk, higher rates of hearing loss were observed in patients with TED or GD compared with the GP. Across cohorts, male patients consistently showed higher cumulative incidence, incidence, and prevalence of hearing loss compared with females, with sex differences most pronounced in the TED cohort. These findings suggest that autoimmune and inflammatory processes may contribute to auditory dysfunction even in young individuals, especially males, with TED or GD, highlighting the importance of patient counseling and proactive monitoring. To our knowledge, this is the first large-scale, population-based investigation to evaluate hearing loss among patients with TED or GD relative to the GP using a US claims database. The findings extend existing evidence that thyroid autoimmunity has systemic manifestations beyond ocular involvement, highlighting the need for further research into underlying pathophysiological mechanisms. The observed rates in the GP cohort were consistent with prior large-scale epidemiologic estimates, lending external validity. 4, 21 For example, Smith et al. (2025) reported prevalence rates of ear-related diagnostic codes as high as 33% in TED and 24% in GD. 4 Other reports have shown a higher baseline prevalence of hearing loss claims in TED (36.6%) compared with GD (30.8%) and the GP (27.3%). 21 In our study, patients with TED and GD were generally older and more often female than the GP, consistent with prior observations of a female-to-male ratio ranging from 2:1 to 4:1 in thyroid-related autoimmune disease. 21 Patients with TED also had greater burden of concurrent conditions, particularly cardiometabolic conditions, and higher use of ototoxic medications. Although these factors are likely to contribute to the elevated risk of hearing loss, the persistence of the association after adjustment suggests that TED may be an independent risk factor. Additional predictors identified included tinnitus, dry eye, and use of aminoglycosides or macrolide antibiotics. While TED is primarily recognized for its ocular and orbital manifestations, the identification of hearing loss, particularly sensorineural subtypes, as a frequent concurrent condition supports its classification as a systemic autoimmune condition with broad physiological impacts. Proposed mechanisms include immune-mediated inflammation, altered cochlear microcirculation, and disruption of neural signaling in the auditory pathway. 11 The high prevalence of concurrent conditions among patients with TED, including type 2 diabetes and hypertension which are both independently associated with hearing loss 2 , 3 , 22 , may compound the overall disease burden through multifactorial pathways. Together, these clinical factors translate into meaningful challenges for patients, as the implications of hearing loss for patient well-being are substantial. Hearing loss can exacerbate communication difficulties, social withdrawal, and psychological distress in a population already challenged by visual and systemic symptoms. 13 – 15 , 23 The findings suggest that a multidisciplinary, cross-specialty approach is necessary to optimize care. Patient education and monitoring may also be valuable, particularly given the potential for under recognition of auditory symptoms and dysfunctions in TED and the multifactorial nature of hearing loss. Awareness of auditory risk in this population, including among young adults and males, as well as informed selection of ototoxic medications, may support timely recognition and intervention, ultimately improving patient outcomes. Among its strengths, this study leveraged a large, longitudinal US claims database, enabling precise estimation of incidence, prevalence, and cumulative incidence across age and sex subgroups. Standardization to the 2020 US population enhanced comparability, and adjustment for concurrent conditions and ototoxic medication use strengthened internal validity. Finally, this analysis was conducted before the approval of teprotumumab and therefore provides baseline epidemiologic data that is not influenced by its use. Limitations include reliance on International Classification of Diseases (ICD) diagnostic codes from insurance claims, which may lead to underreporting or misclassification of hearing loss, particularly in mild or undiagnosed cases. Due to the absence of specific ICD codes for TED, an algorithm was used to identify patients with TED and may be subject to misclassification. The primarily commercially insured population may not fully represent individuals with public insurance or those uninsured. Claims data were missing clinical details such as audiometric measures, TED severity, disease duration, and patient-reported outcomes, limiting characterization of disease impact. The retrospective design prevents determination of causality or temporal sequencing between TED and hearing loss. In conclusion, this large population-based study demonstrates that patients with TED face a significantly elevated risk of hearing loss, particularly of the sensorineural subtype, even in young, low-risk populations. These findings support recognition of TED as a systemic autoimmune disease with auditory implications, highlight the need for continued investigation into underlying mechanisms, and suggest patient education and monitoring may help reduce the unrecognized burden of hearing loss in this population. Future large-scale prospective studies are warranted to clarify causal pathways between thyroid disease and hearing loss, differentiate subtypes such as sensorineural and conductive, and assess the impact of thyroid-directed therapies (e.g., antithyroid drugs, corticosteroids, teprotumumab) on auditory outcomes. Advancing knowledge in this area is critical to shaping comprehensive care pathways and ultimately improving long-term outcomes for patients with TED. Abbreviations AD Alzheimer’s disease CCI Charlson Comorbidity Index CI confidence interval CKD chronic kidney disease,COPD,chronic obstructive pulmonary disease GD Graves’ disease GP general population HR hazard ratio ICD International Classification of Diseases ICD-9-CM International Classification of Diseases,Ninth Revision,Clinical Modification ICD-10-CM International Classification of Diseases,Tenth Revision,Clinical Modification IQR interquartile range N number of patients NSAID nonsteroidal anti-inflammatory drug SD standard deviation SNHL sensorineural hearing loss TED thyroid eye disease US United States WCG® IRB Western Institutional Review Board-Copernicus Group. Declarations Ethics approval and consent to participate Not applicable Consent for publication Not applicable Availability of data and materials The dataset supporting the conclusions of this article is available in the Merative™ MarketScan® Research Databases. Restrictions apply to the availability of these data, which were used under license for the current study and are therefore not publicly available. Data may be obtained from the authors upon reasonable request and with permission from Merative. Competing interests JAB: Amgen (consultant). VM: Amgen (consultant), Viridian Therapeutics Inc. (consultant), Coppersmith Brockelman Lawyers (consultant), hearX SA (Pty) Ltd (advisory board). JM: Amgen (employment and stock ownership). DC: Amgen (contractor). PF: Amgen (employment and stock ownership). HP: Amgen (employment and stock ownership). Funding This work was supported by Amgen Inc., USA. The sponsor participated in the design of the study, conducting the study, interpretation of the data, and review or approval of the manuscript. Authors’ contributions JAB, VM, JM, DC, PF, and HP contributed to study conceptualization and methodology. JM, DC, PF, and HP acquired funding, conducted the investigation, developed the software, performed formal analysis, validation, and visualization, were responsible for project administration, and contributed to writing and review of the manuscript. All authors reviewed and approved the final draft. Acknowledgments Medical writing and editorial assistance was provided by Lorena Tonarelli, MSc, of LT Medical & Value Communications Ltd, and funded by Amgen Inc. Previous presentations The authors disclose that part of the work described in this manuscript was previously presented as a poster at the American Academy of Ophthalmology (AAO) Annual Meeting 2025, held October 18-20, 2025, Orlando, FL, USA. References Toro-Tobon D, Stan MN et al. Graves' Disease and the Manifestations of Thyrotoxicosis. In: Feingold KR, Ahmed SF, Anawalt B, Blackman MR, Boyce A, Chrousos G, editors. Endotext. South Dartmouth (MA)2000. Wei Y, Li X, Cui R, Liu J, Wang G. Associations between sensitivity to thyroid hormones and insulin resistance in euthyroid adults with obesity. Front Endocrinol (Lausanne). 2024;15:1366830. Su T, Gan Y, Ma S, Wu H, Lu S, Zhi M, et al. Graves' disease and the risk of five autoimmune diseases: A Mendelian randomization and colocalization study. Diabetes Metab Syndr. 2024;18(5):103023. Smith TJ, Holt RJ, Fu Q, Qashqai A, Barretto N, Conrad E, et al. Assessment of hearing dysfunction in patients with Graves’ disease and thyroid eye disease without or with teprotumumab. J Clin Endocrinol Metab. 2025;110(3):811–9. Shah SS, Patel BC. Thyroid Eye Disease. StatPearls. Treasure Island (FL)2025. Kulbay M, Tanya SM, Tuli N, Dahoud J, Dahoud A, Alsaleh F, et al. A comprehensive review of thyroid eye disease pathogenesis: from immune dysregulations to novel diagnostic and therapeutic approaches. Int J Mol Sci. 2024;25(21):11628. Berker D, Karabulut H, Isik S, Tutuncu Y, Ozuguz U, Erden G, et al. Evaluation of hearing loss in patients with Graves’ disease. Endocrine. 2012;41(1):116–21. Mahafzah M, Mahafza T, Omari H, Al Hawari H. Investigating the possible audiological effects of hypothyroidism. J Phonet Audiol. 2018;4:1. Mahafzah M, Al Hawari H, Momani M, Abbasi N. The prevalence of hearing loss in patients with autoimmune thyroid disease: a prospective study. J Med J. 2018;52(3):109–16. Tsai Y-T, Chang I-J, Hsu C-M, Yang Y-H, Liu C-Y, Tsai M-S, et al. Association between sudden sensorineural hearing loss and preexisting thyroid diseases: a nationwide case-control study in Taiwan. Int J Environ Res Public Health. 2020;17(3):834. Athanasopoulos M, Samara P, Athanasopoulos I. Decoding the impact of autoinflammatory/autoimmune diseases on inner ear harmony and hearing loss. Explor Immunol. 2024;4(1):73–89. Rizk HG, Lee JA, Liu YF, Endriukaitis L, Isaac JL, Bullington WM. Drug-Induced Ototoxicity: A Comprehensive Review and Reference Guide. Pharmacotherapy. 2020;40(12):1265–75. Lawrence BJ, Jayakody DM, Bennett RJ, Eikelboom RH, Gasson N, Friedland PL. Hearing loss and depression in older adults: a systematic review and meta-analysis. Gerontologist. 2020;60(3):e137–54. Nordvik Ø, Laugen Heggdal PO, Brännström J, Vassbotn F, Aarstad AK, Aarstad HJ. Generic quality of life in persons with hearing loss: a systematic literature review. BMC Ear Nose Throat Disord. 2018;18(1):1. Bigelow RT, Reed NS, Brewster KK, Huang A, Rebok G, Rutherford BR, et al. Association of hearing loss with psychological distress and utilization of mental health services among adults in the United States. JAMA Netw Open. 2020;3(7):e2010986–e. Shafiepour M, Bamdad Z, Radman M. Prevalence of hearing loss among patients with type 2 diabetes. J Med Life. 2022;15(6):772–7. Ramage-Morin PL, Banks R, Pineault D, Atrach M, Gilmour H. Hypertension associated with hearing health problems among Canadian adults aged 19 to 79 years. Health Rep. 2021:1209–367. Delhez A, Lefebvre P, Péqueux C, Malgrange B, Delacroix L. Auditory function and dysfunction: estrogen makes a difference. Cell Mol Life Sci. 2020;77(4):619–35. Wang Y, Mei P, Zhao Y, et al. Associations Between Occupational Noise Exposure, Aging, and Gender and Hearing Loss: A Cross-Sectional Study in China. Audiol Res. 2025;15(4):91. Azuero A. A note on the magnitude of hazard ratios. Cancer. 2016;122(8):1298–9. Smith T, Meyers A, Fu Q, Holt R, Zhu K. 8518. Prevalence of Hearing Dysfunction in Patients with Autoimmune Thyroid Disorders, Thyroid Eye Disease and the General US population: A Claims Database Analysis. J Endocr Soc. 2024;8:A1069. Toyama K, Mogi M. Hypertension and the development of hearing loss. Hypertens Res. 2022;45(1):172–4. Loughrey DG, Kelly ME, Kelley GA, Brennan S, Lawlor BA. Association of age-related hearing loss with cognitive function, cognitive impairment, and dementia: a systematic review and meta-analysis. JAMA Otolaryngol Head Neck Surg. 2018;144(2):115–26. Additional Declarations Competing interest reported. JAB: Amgen (consultant). VM: Amgen (consultant), Viridian Therapeutics Inc. (consultant), Coppersmith Brockelman Lawyers (consultant), hearX SA (Pty) Ltd (advisory board). JM: Amgen (employment and stock ownership). DC: Amgen (contractor). PF: Amgen (employment and stock ownership). HP: Amgen (employment and stock ownership). Supplementary Files HearingLossAdditionalmaterialTEDBMCED20JAN26.docx Additional Table 1 File format: Word Title: Age- and sex-standardized cumulative incidence, incidence rates, and prevalence of hearing loss subcategories Description: Table summarizing age- and gender-standardized cumulative incidence, incidence rates, and prevalence of hearing loss (composite outcome) subcategories across study cohorts. Additional Table 2 File format: Word Title: Code list for patient selection and hearing loss Description: Table summarizing ICD-9-CM & ICD-10-CM codes used to identify study cohorts and primary outcomes Additional Figure 1 File format: Word Title: Predictors of sensorineural hearing loss Description: Graph showing the hazard ratios associated with predictors of sensorineural hearing loss Additional Figure 2 File format: Word Title: Risk of sensorineural hearing loss over time Description: Kaplan-Meier estimates of risk of hearing loss over time across study cohorts Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 17 Mar, 2026 Reviewers invited by journal 05 Mar, 2026 Editor invited by journal 09 Feb, 2026 Editor assigned by journal 06 Feb, 2026 Submission checks completed at journal 06 Feb, 2026 First submitted to journal 05 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8801141","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":602508846,"identity":"6bf28f7f-c057-4459-8f55-7f38d2c672e6","order_by":0,"name":"Jason A. Brant","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvUlEQVRIiWNgGAWjYBAC9gYeMC3HwAymmQlrYYRoMTAmXUtiAwPRWtrPHvvwc8ef9A3H2R9+YKiwhunFo6UnL3lm7xmD3A2HeYwlGM6kE6GlIceYgbfNIHfbYR42Bsa2w0Ro6X9jzPi3zSDd7DD7MwbGf0RoEZyRY8wMtCXB7DCDGdBOIrRIS7xLZpZtMzbcD/JLwrF0Y4Ja+PhzDzO+bZOTl+w//vDDhxprWYJaUEECacpHwSgYBaNgFOACAA5BOcDo3gNHAAAAAElFTkSuQmCC","orcid":"","institution":"University of Wisconsin","correspondingAuthor":true,"prefix":"","firstName":"Jason","middleName":"A.","lastName":"Brant","suffix":""},{"id":602508848,"identity":"fad23b97-7287-42bd-8ca9-33461077612e","order_by":1,"name":"Vinaya Manchaiah","email":"","orcid":"","institution":"University of Colorado School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Vinaya","middleName":"","lastName":"Manchaiah","suffix":""},{"id":602508849,"identity":"6e20ea7c-289f-4645-b305-8286ba497a42","order_by":2,"name":"Junjie Ma","email":"","orcid":"","institution":"Amgen Inc","correspondingAuthor":false,"prefix":"","firstName":"Junjie","middleName":"","lastName":"Ma","suffix":""},{"id":602508851,"identity":"f336be27-af6d-4635-b1f6-fa5342326f1c","order_by":3,"name":"Deepika Chauhan","email":"","orcid":"","institution":"Amgen Inc","correspondingAuthor":false,"prefix":"","firstName":"Deepika","middleName":"","lastName":"Chauhan","suffix":""},{"id":602508852,"identity":"2a501ab1-edf2-4276-8e4b-121aee8aa68c","order_by":4,"name":"Patricia Franco","email":"","orcid":"","institution":"Amgen Inc","correspondingAuthor":false,"prefix":"","firstName":"Patricia","middleName":"","lastName":"Franco","suffix":""},{"id":602508854,"identity":"4105a5b9-8c0a-4a2b-84a9-6da4dacad5eb","order_by":5,"name":"Haridarshan Patel","email":"","orcid":"","institution":"Amgen Inc","correspondingAuthor":false,"prefix":"","firstName":"Haridarshan","middleName":"","lastName":"Patel","suffix":""}],"badges":[],"createdAt":"2026-02-05 22:53:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8801141/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8801141/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104405410,"identity":"d660e379-0df5-4f01-be80-d910e3021d98","added_by":"auto","created_at":"2026-03-11 12:22:49","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":180949,"visible":true,"origin":"","legend":"\u003cp\u003eStudy design\u003c/p\u003e\n\u003cp\u003eSchema illustrating key elements and timing of the study design.\u003c/p\u003e\n\u003cp\u003eGD, Graves’ disease; GP, general population; TED, thyroid eye disease.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8801141/v1/a22784f0ba462967392c7875.png"},{"id":104406178,"identity":"60a50df5-9cdc-4d4f-ab2b-5f5f91d96259","added_by":"auto","created_at":"2026-03-11 12:24:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":173645,"visible":true,"origin":"","legend":"\u003cp\u003ePredictors of hearing loss\u003c/p\u003e\n\u003cp\u003eGraph showing the hazard ratios associated with predictors of hearing loss.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eOnly clinically meaningful predictors (HR ≥1.3) of hearing loss are displayed. Other predictors (HR\u0026gt;1.0) included: GD, baseline concurrent conditions (i.e., psoriasis, systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, glaucoma, ocular hypertension, obesity, dyslipidemia/hyperlipidemia, mental health disorders, ischemic heart disease, vitamin D deficiency), and use of ototoxic medications (i.e., salicylates, nonsteroidal anti-inflammatory drugs, opioids, quinine-based medications). Additional variables (i.e., non-predictors) included in the model were as follows: geographic region, baseline concurrent conditions (i.e., type 2 diabetes, smoking or nicotine dependency, hypertension, chronic obstructive pulmonary disease [COPD], chronic kidney disease [CKD] without dialysis, non-AD dementia, hyperglycemia), and use of ototoxic medications (i.e., erythromycin, loop diuretics, chemotherapy drugs).\u003c/p\u003e\n\u003cp\u003eCI, confidence interval; HR, hazard ratio; TED, thyroid eye disease.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8801141/v1/db65957b364a6ee91c602621.png"},{"id":104343858,"identity":"089774b9-f4a9-4fd1-88b9-a3382ac37001","added_by":"auto","created_at":"2026-03-10 17:16:29","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":115270,"visible":true,"origin":"","legend":"\u003cp\u003eRisk of hearing loss over time\u003c/p\u003e\n\u003cp\u003eKaplan-Meier estimates of risk of hearing loss over time across study cohorts.\u003c/p\u003e\n\u003cp\u003eGD, Graves’ disease; GP, general population; TED, thyroid eye disease.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8801141/v1/8a96e69cf66880e0f28754b2.png"},{"id":104409744,"identity":"df2e25c9-30c2-4a07-abc5-2e47b36ae70a","added_by":"auto","created_at":"2026-03-11 12:47:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1337380,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8801141/v1/09660171-a4d0-436f-a2a3-5a4c82417e81.pdf"},{"id":104405459,"identity":"1a216534-da2f-4ea1-8951-c24c13d3cbb6","added_by":"auto","created_at":"2026-03-11 12:22:59","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":483186,"visible":true,"origin":"","legend":"\u003cp\u003eAdditional Table 1\u003c/p\u003e\n\u003cp\u003eFile format: Word\u003c/p\u003e\n\u003cp\u003eTitle:\u003cstrong\u003e \u003c/strong\u003eAge- and sex-standardized cumulative incidence, incidence rates, and prevalence of hearing loss subcategories\u003c/p\u003e\n\u003cp\u003eDescription: Table summarizing age- and gender-standardized cumulative incidence, incidence rates, and prevalence of hearing loss (composite outcome) subcategories across study cohorts\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdditional Table 2\u003c/p\u003e\n\u003cp\u003eFile format: Word\u003c/p\u003e\n\u003cp\u003eTitle: Code list for patient selection and hearing loss\u003c/p\u003e\n\u003cp\u003eDescription: Table summarizing ICD-9-CM \u0026amp; ICD-10-CM codes used to identify study cohorts and primary outcomes\u003c/p\u003e\n\u003cp\u003eAdditional Figure 1\u003c/p\u003e\n\u003cp\u003eFile format: Word\u003c/p\u003e\n\u003cp\u003eTitle: Predictors of sensorineural hearing loss\u003c/p\u003e\n\u003cp\u003eDescription: Graph showing the hazard ratios associated with predictors of sensorineural hearing loss\u003c/p\u003e\n\u003cp\u003eAdditional Figure 2\u003c/p\u003e\n\u003cp\u003eFile format: Word\u003c/p\u003e\n\u003cp\u003eTitle: Risk of sensorineural hearing loss over time\u003c/p\u003e\n\u003cp\u003eDescription: Kaplan-Meier estimates of risk of hearing loss over time across study cohorts\u003c/p\u003e","description":"","filename":"HearingLossAdditionalmaterialTEDBMCED20JAN26.docx","url":"https://assets-eu.researchsquare.com/files/rs-8801141/v1/6fa973ba2b639c2d8500e436.docx"}],"financialInterests":"Competing interest reported. JAB: Amgen (consultant). VM: Amgen (consultant), Viridian Therapeutics Inc. (consultant), Coppersmith Brockelman Lawyers (consultant), hearX SA (Pty) Ltd (advisory board). JM: Amgen (employment and stock ownership). DC: Amgen (contractor). PF: Amgen (employment and stock ownership). HP: Amgen (employment and stock ownership).","formattedTitle":"Epidemiology and risk factors of hearing loss in thyroid eye disease in the United States: A retrospective study of MarketScan® data","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eGraves\u0026rsquo; disease (GD) is a chronic autoimmune disorder of the thyroid gland characterized by excessive thyroid hormone production and release.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Beyond its endocrine manifestations, GD is associated with autoimmune conditions such as systemic rheumatoid arthritis, lupus erythematosus, and type 1 diabetes mellitus.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e It may also impact non-thyroidal organ systems, notably the eyes and ears.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Thyroid eye disease (TED), also known as Graves\u0026rsquo; orbitopathy or thyroid-associated ophthalmopathy, is the primary extrathyroidal manifestation observed in GD.\u003csup\u003e6\u003c/sup\u003e Typically characterized by inflammation/edema and expansion of extraocular muscles causing proptosis, diplopia and pain,\u003csup\u003e6\u003c/sup\u003e TED has recently been associated with hearing dysfunction.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn a large population-based study, adjusted analyses showed that sudden sensorineural hearing loss (SNHL) had 54% higher odds in individuals with hypothyroidism and 41% higher odds in those with hyperthyroidism, compared with matched controls without thyroid disease.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e A cross-sectional, case-control study found worse high-frequency hearing ability in patients with newly diagnosed GD, compared with healthy controls.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Recent analyses have also documented audiometric abnormalities in GD and TED, irrespective of medication use, with decreased high-frequency sensitivity and mild-to-moderate SNHL reported in up to 23.5% of patients, further strengthening the evidence that thyroid autoimmunity affects the auditory system.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAlthough the exact pathophysiology is not fully understood, several mechanisms have been proposed to explain the link between thyroid autoimmunity and auditory dysfunction. Autoimmune-mediated inflammation may cause damage to cochlear hair cells or interfere with synaptic transmission, leading to SNHL.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Systemic inflammatory vascular changes could similarly compromise cochlear perfusion, resulting in ischemic injury and impaired auditory function.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Ototoxicity from thyroid medications has also been proposed as a contributing factor.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eRegardless of the underlying pathophysiology, hearing impairment carries a substantial personal and societal burden. It limits communication and social interaction, adversely affecting relationships, occupational performance, and mental health, with established links to depression, cognitive impairment, and poor quality of life.\u003csup\u003e\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e In the context of GD and TED, recognition of hearing loss is particularly important, as it can potentially exacerbate the psychosocial burden already associated with these disorders.\u003c/p\u003e \u003cp\u003eSeveral comorbidities commonly associated with GD and TED contribute to the risk of hearing dysfunction in these conditions. Type 2 diabetes can cause auditory impairment through microvascular and neuropathic changes affecting cochlear and auditory nerve function.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Hypertension can damage cochlear microvasculature, particularly the stria vascularis, impairing perfusion.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e Additionally, male sex at birth has been consistently associated with a high prevalence of hearing impairment, owing to lifetime occupational noise exposure and the absence of estrogen\u0026rsquo;s protective effects.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e These overlapping metabolic, vascular, and epidemiological factors may act synergistically in GD and TED, heightening the risk of auditory dysfunction and potentially contributing to irreversible impairment if unrecognized.\u003c/p\u003e \u003cp\u003eDespite emerging evidence showing higher rates of sudden SNHL in hypothyroidism and hyperthyroidism, important gaps in knowledge remain. Existing studies are small, cross-sectional, or descriptive, which limits the ability to draw causal inferences. Few investigations differentiate between types of hearing impairment, such as sensorineural versus conductive hearing loss, thereby constraining mechanistic insights. In addition, research on the effects of thyroid-related treatments, including antithyroid drugs, corticosteroids, and teprotumumab, on auditory outcomes is lacking.\u003c/p\u003e \u003cp\u003eThere remains a clear need for large-scale studies to characterize hearing loss among patients with GD and TED. This study aimed to quantify the real-world cumulative incidence, incidence rates, and prevalence of hearing loss in the United States (US) using a large administrative claims database. A further aim was to evaluate longitudinal risk and predictors of hearing loss, comparing outcomes in patients with either condition to those in the general population (GP).\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData source and design\u003c/h2\u003e \u003cp\u003eThis was a retrospective, multi-cohort study of longitudinal medical and pharmacy de-identified patient data from the Merative\u0026trade; MarketScan\u0026reg; Research Claims Database (January 1, 2014\u0026ndash;December 31, 2019).\u003c/p\u003e \u003cp\u003ePatients were categorized into three cohorts. The TED cohort included patients with \u0026ge;\u0026thinsp;1 claim for GD and an eye manifestation (i.e., diplopia, lid retraction, strabismus, exophthalmos) within a 12-month interval (index date: latter observed claim of the first code for GD or eye manifestation). The GD cohort included patients with \u0026ge;\u0026thinsp;2 outpatient GD diagnoses\u0026thinsp;\u0026gt;\u0026thinsp;30 days apart, or \u0026ge;\u0026thinsp;1 inpatient GD diagnosis without qualifying TED features (index date: first observed claim with a GD diagnosis code). Individuals with \u0026ge;\u0026thinsp;1 claim who did not meet criteria for GD or TED were included in the GP cohort (index date: first eligible medical claim).\u003c/p\u003e \u003cp\u003eEligible patients were required to be \u0026ge;\u0026thinsp;18 years old with continuous health plan enrollment for \u0026ge;\u0026thinsp;12 months before and \u0026ge;\u0026thinsp;6 months after the index date, allowing for gaps of \u0026lt;\u0026thinsp;45 days. The baseline period was the 12 months prior to the index date, and the follow-up period extended from index until the earliest of occurrence of hearing loss, health plan disenrollment, death, or end of data availability. Patients with a diagnosis of hearing loss during the baseline period were excluded from incidence analyses (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eOutcome measures\u003c/h3\u003e\n\u003cp\u003eThe primary outcome was hearing loss, defined as a composite of conductive hearing loss, SNHL, mixed conductive and SNHL, age-related hearing loss, and other hearing loss (i.e., sudden hearing loss, unspecified hearing loss, other specified hearing loss). SNHL was evaluated as a secondary outcome.\u003c/p\u003e \u003cp\u003eFor each cohort, baseline demographic and clinical characteristics were estimated, with concurrent conditions defined as \u0026ge;\u0026thinsp;2 outpatient or \u0026ge;\u0026thinsp;1 inpatient code of interest. We also estimated hearing loss cumulative incidence, incidence rates per 10,000 person-years, and prevalence; each measure was standardized to the 2020 US standard population by age and sex at birth (sex) using the most recent census distribution available to enhance comparability across cohorts and account for differences versus the US population.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eBaseline demographic and clinical characteristics were summarized descriptively, using means and medians with standard deviation (SD) for continuous variables and frequency counts with percentages for categorical variables. Standardized cumulative incidence (%), incidence rates (per 10,000 person-years), and prevalence (%) of hearing loss were descriptively reported for each cohort (TED, GD, and GP). Additional subgroup analyses were conducted to summarize cumulative incidence (%), incidence rates (per 10,000 person-years), and prevalence (%) of hearing loss by age and sex. Missing data were handled by excluding unknown values for continuous variables, whereas categorical variables comprised an \u0026lsquo;unknown\u0026rsquo; category.\u003c/p\u003e \u003cp\u003eCox proportional hazards models were used to estimate the risk and predictors of hearing loss, adjusting for age, sex, geographic region, concurrent conditions, and use of ototoxic medications including salicylates, macrolide antibiotics, and aminoglycosides. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were reported, with an HR\u0026thinsp;\u0026ge;\u0026thinsp;1.3 indicating clinically meaningful predictors (i.e., increasing the relative risk of an event by \u0026ge;\u0026thinsp;30%).\u003csup\u003e20\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eKaplan-Meier methods were used to estimate time to hearing loss; patients were censored at their last recorded observation or at the end of the study period. The evaluation of time-to-event risk and predictors was replicated for the SNHL subcategory. All analyses were performed using Spark SQL on Databricks and SAS 9.4.\u003c/p\u003e \u003cp\u003eThis study was deemed exempt by the Western Institutional Review Board-Copernicus Group (WCG\u0026reg; IRB) under 45 CFR \u0026sect;\u0026nbsp;46.104(d)(4) due to the retrospective study design, anonymized nature of the data analyzed, and low risk of confidentiality breach.\u003c/p\u003e \u003cp\u003e This retrospective study was conducted in accordance with the Declaration of Helsinki and applicable regulatory requirements. As it involved analysis of de-identified data, no direct patient contact occurred and informed consent was not required.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eBaseline patient characteristics\u003c/h2\u003e \u003cp\u003eA total of 20,493,563 (TED: 38,723; GD: 171,831; GP: 20,283,009) patients met criteria for inclusion. Patient demographics and clinical characteristics by cohort are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Mean (SD) age was 55.2 (15.5) years in TED, 52.8 (15.7) in GD, and 47.4 (16.8) in GP. Females accounted for 79.8%, 78.2%, and 53.3% in TED, GD, and the GP, respectively. Commercial insurance was the predominant type of coverage across all cohorts, with rates of 72.6% in TED, 77.9% in GD, and 83.9% in GP.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline patient demographics and clinical characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTED\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;38723\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGD\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;171831\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGP\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;20283009\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eDemographics\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD [median]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55.2\u0026thinsp;\u0026plusmn;\u0026thinsp;15.5 [56.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52.8\u0026thinsp;\u0026plusmn;\u0026thinsp;15.7 [53.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47.4\u0026thinsp;\u0026plusmn;\u0026thinsp;16.8 [48.0]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge group, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u0026ndash;35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4394 (11.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25253 (14.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5436970 (26.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e36\u0026ndash;45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5432 (14.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28669 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3632842 (17.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e46\u0026ndash;55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9061 (23.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41942 (24.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4429317 (21.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e56\u0026ndash;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11459 (29.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46192 (26.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4283453 (21.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e66\u0026ndash;75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4292 (11.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15017 (8.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1420819 (7.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e76\u0026ndash;85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2887 (7.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10053 (5.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e766465 (3.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1198 (3.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4705 (2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e313143 (1.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eSex, n (%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7807 (20.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37391 (21.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9468582 (46.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30916 (79.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e134440 (78.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10814427 (53.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eGeographic region\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e, n (%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSouth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12165 (39.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57802 (40.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6495435 (36.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNortheast\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7887 (25.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32581 (22.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3920869 (21.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNorth Central\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6192 (20.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29353 (20.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3975533 (22.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWest\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4529 (14.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24181 (16.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3488840 (19.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHealth plan, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCommercial only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28123 (72.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e133830 (77.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17027411 (83.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedicare only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5354 (13.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19625 (11.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1619437 (8.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBoth Commercial \u0026amp; Medicare\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5246 (13.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18376 (10.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1636161 (8.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eClinical characteristics\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCCI, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD [median]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.6 (1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.4 (1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.2 (0.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eConcurrent conditions\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e, n (%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17733 (45.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68727 (40.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4443305 (21.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDyslipidemia/Hyperlipidemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16642 (43.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61657 (35.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4059124 (20.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObesity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7756 (20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25170 (14.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e909438 (4.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMental health disorders\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7513 (19.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22649 (13.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1024304 (5.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType 2 diabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6942 (17.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27506 (16.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1718302 (8.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin D deficiency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6895 (17.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21906 (12.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e666668 (3.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIschemic heart disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3880 (10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12959 (7.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e803268 (4.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking or nicotine dependency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4127 (10.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13079 (7.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e553080 (2.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDry eye\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3515 (9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4452 (2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e203842 (1.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOPD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3101 (8.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10610 (6.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e487683 (2.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCKD without dialysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3139 (8.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10020 (5.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e456961 (2.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyperglycemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1473 (3.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3398 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6353 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlaucoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1241 (3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3196 (1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e262912 (1.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMuscle spasms (symptomatic presentation)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1266 (3.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3964 (2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e233024 (1.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRheumatoid arthritis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1088 (2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3084 (1.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e165178 (0.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType 1 diabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1053 (2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4153 (2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e188731 (0.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-AD dementia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e577 (1.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1793 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70083 (0.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOcular hypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e451 (1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e824 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e52319 (0.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystemic lupus erythematosus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e424 (1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e905 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40068 (0.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePsoriasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e436 (1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1306 (0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e102544 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eMedication use\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e, n (%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNSAIDs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15178 (39.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55220 (32.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4054589 (20.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOpioids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10321 (26.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34056 (19.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2095105 (10.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMacrolide antibiotics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8643 (22.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29672 (17.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2054492 (10.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAminoglycosides\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3476 (9.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6306 (3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e442902 (2.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLoop diuretics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2659 (6.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9188 (5.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e412419 (2.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eErythromycin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1130 (2.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1669 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e123463 (0.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSalicylates\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e955 (2.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2599 (1.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e154269 (0.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQuinine based medications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e610 (1.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1482 (0.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e80638 (0.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChemotherapy drugs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e564 (1.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1792 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e106031 (0.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eFollow-up period\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of follow-up period (years), median [IQR]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.9 (1.0, 3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.0 (1.0, 3.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.0 (0.9, 4.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eTable summarizing baseline patient demographics, clinical characteristics, and study period across study cohorts\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003e1\u003c/sup\u003eProportions were calculated among patients with data availability. \u003csup\u003e2\u003c/sup\u003eCategories are not mutually exclusive. \u003csup\u003e3\u003c/sup\u003eIncludes anxiety, major depressive disorder, stress, dysthymic disorder, panic disorder, bipolar, mood disorder, phobia, nervousness, dementia, and manic disorder.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eAD, Alzheimer\u0026rsquo;s disease; CCI, Charlson Comorbidity Index; CKD, chronic kidney disease, COPD, chronic obstructive pulmonary disease; GD, Graves\u0026rsquo; disease; GP, general population; IQR, interquartile range; N, number of patients; NSAID, nonsteroidal anti-inflammatory drug; SD, standard deviation; TED, thyroid eye disease.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e[Please insert Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e here]\u003c/p\u003e \u003cp\u003eCommon baseline concurrent conditions included hypertension (TED: 45.8%; GD: 40.0%; GP: 21.9%), hyperlipidemia (TED: 43.0%; GD: 35.9%; GP: 20.0%), obesity (TED: 20.0%, GD: 14.6%; GP: 4.5%), emotional stress (TED: 19.4%; GD: 13.2%; GP: 5.1%), and vitamin D deficiency (TED: 17.8%; GD: 12.7%; GP: 3.3%).\u003c/p\u003e \u003cp\u003eIn terms of baseline ototoxic medication use, nonsteroidal anti-inflammatory drugs (NSAIDs) were used by 39.2% of patients in the TED cohort, and by 32.1% and 20.0% in the GD and GP cohorts, respectively. Opioid use was 26.7%, 19.8%, and 10.3%, in TED, GD and GP, and macrolide antibiotic use was 22.3%, 17.3%, and 10.1%.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eHearing loss incidence and prevalence\u003c/h2\u003e \u003cp\u003eAfter standardization by age and sex, incidence of hearing loss was 142.2 per 10,000 person-years in TED, 92.0 per 10,000 person-years in GD, and 67.6 per 10,000 person-years in GP (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Cumulative incidence for TED, GD, and GP was 2.8%, 2.0% and 1.6%, respectively; prevalence was 4.6%, 3.0% and 2.2%. Among subtypes of hearing loss, SNHL had the greatest cumulative incidence across all 3 cohorts, with 2.1% in TED, 1.4% in GD, and 1.1% in GP, with other types including conductive (0.4%, 0.2%, 0.1%), mixed conductive-sensorineural (0.2%, 0.2%, 0.1%), and other hearing loss (0.9%, 0.7%, 0.5%) (\u003cb\u003eAdditiona\u003c/b\u003e Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAge- and gender-standardized cumulative incidence, incidence rates, and prevalence of hearing loss\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTED\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;38723\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGD\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;171831\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGP\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;20283009\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCumulative incidence, % (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.8% (2.6%, 3.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.0% (1.9%, 2.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.6% (1.6%, 1.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncidence, per 10000 person-years (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e142.2 (132.3,152.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e92.0 (88.2, 95.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e67.6 (67.3, 67.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevalence, % (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.6% (4.4%, 4.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.0% (2.9%, 3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.2% (2.2%, 2.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eTable summarizing age- and gender-standardized cumulative incidence, incidence rates, and prevalence of hearing loss (composite outcome) across study cohorts.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eCI, confidence interval; GD: Graves\u0026rsquo; disease; GP, general population; N, number of patients; TED, thyroid eye disease.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e[Please insert Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e here]\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSubgroup analyses\u003c/h3\u003e\n\u003cp\u003eCumulative incidence of hearing loss increased with age in all cohorts, from 0.8%, 0.4%, and 0.3% at 18\u0026ndash;35 years to 11.5%, 8.9%, and 7.3% at \u0026ge;\u0026thinsp;86 years in TED, GD, and GP, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). When stratified by sex, among males the cumulative incidence of hearing loss was 4.3% in TED, 2.5% in GD, and 1.6% in GP, compared with 3.0%, 2.0%, and 1.3% in females (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCumulative incidence, incidence, and prevalence of hearing loss stratified by age and sex\\\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTED\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;38723\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGD\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;171831\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGP\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;20283009\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eAge groups\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCumulative incidence, % (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u0026ndash;35 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.8% (0.6%, 1.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.4% (0.3%, 0.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.3% (0.3%, 0.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e36\u0026ndash;45 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.4% (1.1%, 1.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.8% (0.7%, 0.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.6% (0.6%, 0.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e46\u0026ndash;55 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.1% (1.8%, 2.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.4% (1.3%, 1.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.2% (1.2%, 1.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e56\u0026ndash;65 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.9% (2.6%, 3.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.2% (2.1%, 2.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.9% (1.9%, 1.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e66\u0026ndash;75 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.7% (5.0%, 6.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.2% (3.8%, 4.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.6% (3.6%, 3.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e76\u0026ndash;85 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.0% (8.0%, 10.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.5% (6.0%, 7.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.7% (5.7%, 5.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;86 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.5% (9.6%, 13.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.9% (8.1%, 9.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.3% (7.2%, 7.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncidence, per 10000 person-years (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u0026ndash;35 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39.9 (39.9, 39.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19.4 (19.4, 19.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.0 (13.0, 13.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e36\u0026ndash;45 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64.4 (44.8, 84.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32.4 (32.4, 32.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23.1 (23.1, 23.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e46\u0026ndash;55 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e91.6 (91.6, 91.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55.6 (55.6, 55.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42.2 (42.2, 42.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e56\u0026ndash;65 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e137.9 (118.3, 157.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95.7 (95.7, 95.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e73.4 (73.4, 73.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e66\u0026ndash;75 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e286.8 (252.9, 320.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e195.8 (176.2, 215.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e158.0 (158.0, 158.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e76\u0026ndash;85 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e480.6 (421.8, 539.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e315.7 (288.0, 343.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e241.7 (241.7, 241.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;86 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e659.5 (546.9, 772.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e493.1 (445.0, 541.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e348.2 (348.2, 348.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevalence, % (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u0026ndash;35 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.3% (1.0%, 1.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.7% (0.6%, 0.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.4% (0.4%, 0.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e36\u0026ndash;45 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.3% (1.9%, 2.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.1% (1.0%, 1.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.8% (0.8%, 0.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e46\u0026ndash;55 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.3% (2.9%, 3.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.0% (1.8%, 2.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.5% (1.5%, 1.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e56\u0026ndash;65 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.9% (4.5%, 5.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.2% (3.1%, 3.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.5% (2.5%, 2.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e66\u0026ndash;75 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.5% (8.6%, 10.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.4% (6.0%, 6.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.1% (5.1%, 5.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e76\u0026ndash;85 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.0% (12.7%, 15.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.8% (9.3%, 10.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.3% (8.2%, 8.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;86 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17.7% (15.5%, 19.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.5% (12.5%, 14.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.9% (10.7%, 11.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCumulative incidence, % (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.3% (3.8%, 4.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.5% (2.4%, 2.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.6% (1.6%, 1.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.0% (2.8%, 3.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.0% (1.9%, 2.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.3% (1.3%, 1.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncidence, per 10000 person-years (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e204.7 (185.1, 224.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e111.4 (111.4, 111.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61.8 (61.8, 61.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e139.6 (139.6, 139.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e84.2 (84.2, 84.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50.1 (50.1, 50.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevalence, % (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.2% (6.7%, 7.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.0% (3.8%, 4.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.1% (2.1%, 2.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.8% (4.6%, 5.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.9% (2.8%, 3.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.8% (1.8%, 1.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eTable summarizing the cumulative incidence, incidence, and prevalence of hearing loss (composite outcome) stratified by age groups and sex across study cohorts.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eCI, confidence interval; GD: Graves\u0026rsquo; disease; GP, general population; N, number of patients; TED, thyroid eye disease.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e[Please insert Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e here]\u003c/p\u003e\n\u003ch3\u003eRisk and predictors of hearing loss\u003c/h3\u003e\n\u003cp\u003eIn unadjusted analyses, the HR for hearing loss was 2.6 (95% CI, 2.5\u0026ndash;2.8) in the TED cohort and 1.6 (95% CI, 1.5\u0026ndash;1.6) in the GD cohort, relative to the GP. After adjustment for patient characteristics, the HR remained elevated at 1.6 (95% CI, 1.5\u0026ndash;1.7) in TED and 1.2 (95% CI, 1.2\u0026ndash;1.3) in GD, corresponding to a 60% and 20%, respectively, higher risk of hearing loss.\u003c/p\u003e \u003cp\u003eIndependent key predictors of hearing loss with HRs\u0026thinsp;\u0026ge;\u0026thinsp;1.3 included advanced age, male sex, selected concurrent conditions such as tinnitus, dry eye, and muscle spasms, as well as use of ototoxic medications including aminoglycosides and macrolide antibiotics (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Kaplan-Meier curves demonstrated a progressive increase in risk of hearing loss over time across all cohorts, with the TED and GD curves consistently above that of the GP cohort (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn subgroup analyses, the unadjusted HR for SNHL was 2.9 (95% CI, 2.7\u0026ndash;3.1) in the TED cohort and 1.6 (95% CI, 1.5\u0026ndash;1.7) in the GD cohort, relative to the GP cohort. After adjustment, the HR was 1.7 (95% CI, 1.6\u0026ndash;1.8) in TED and 1.2 (95% CI, 1.2\u0026ndash;1.3) in GD, corresponding to a 70% and 20%, respectively, higher risk of SNHL versus the GP cohort.\u003c/p\u003e \u003cp\u003eKey predictors of SNHL (HR\u0026thinsp;\u0026ge;\u0026thinsp;1.3) mirrored those identified in the main analysis of overall hearing loss and included advanced age, male sex, concurrent conditions such as tinnitus, dry eye, and muscle spasms, as well as use of ototoxic medications including aminoglycosides and macrolide antibiotics. Additional predictors unique to SNHL were ocular hypertension and psoriasis (\u003cb\u003eAdditional\u003c/b\u003e Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Kaplan-Meier curves showed a progressive increase in SNHL risk over time across all cohorts, with the TED and GD curves being consistently higher than those of the GP (\u003cb\u003eAdditional\u003c/b\u003e Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe results of this large-scale, real-world study highlight a consistent association between thyroid autoimmunity and auditory dysfunction. Across all outcome metrics, including incidence, cumulative incidence, and prevalence, patients with TED consistently showed the greatest burden of hearing loss compared to those with GD and the GP. In unadjusted analyses, patients with TED had more than twice the risk of hearing loss relative to the GP (HR 2.6; 95% CI, 2.5\u0026ndash;2.8). This association remained significant after adjustment for age, sex, concurrent conditions, and ototoxic medication use, with a 60% higher risk observed among patients with TED (HR 1.6; 95% CI, 1.5\u0026ndash;1.7). Patients with GD also demonstrated elevated, though comparatively lower than the TED population, risk (adjusted HR 1.2; 95% CI, 1.2\u0026ndash;1.3) for hearing loss. SNHL was the most frequent subtype and the primary contributor to overall incidence and prevalence.\u003c/p\u003e \u003cp\u003eSubgroup analyses confirmed the influence of age, with increasing hearing loss prevalence across all cohorts. Notably, even among young adults aged 18\u0026ndash;35 years, a group generally considered at very low risk, higher rates of hearing loss were observed in patients with TED or GD compared with the GP. Across cohorts, male patients consistently showed higher cumulative incidence, incidence, and prevalence of hearing loss compared with females, with sex differences most pronounced in the TED cohort. These findings suggest that autoimmune and inflammatory processes may contribute to auditory dysfunction even in young individuals, especially males, with TED or GD, highlighting the importance of patient counseling and proactive monitoring.\u003c/p\u003e \u003cp\u003eTo our knowledge, this is the first large-scale, population-based investigation to evaluate hearing loss among patients with TED or GD relative to the GP using a US claims database. The findings extend existing evidence that thyroid autoimmunity has systemic manifestations beyond ocular involvement, highlighting the need for further research into underlying pathophysiological mechanisms.\u003c/p\u003e \u003cp\u003eThe observed rates in the GP cohort were consistent with prior large-scale epidemiologic estimates, lending external validity. \u003csup\u003e4, 21\u003c/sup\u003e For example, Smith et al. (2025) reported prevalence rates of ear-related diagnostic codes as high as 33% in TED and 24% in GD.\u003csup\u003e4\u003c/sup\u003e Other reports have shown a higher baseline prevalence of hearing loss claims in TED (36.6%) compared with GD (30.8%) and the GP (27.3%).\u003csup\u003e21\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn our study, patients with TED and GD were generally older and more often female than the GP, consistent with prior observations of a female-to-male ratio ranging from 2:1 to 4:1 in thyroid-related autoimmune disease.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e Patients with TED also had greater burden of concurrent conditions, particularly cardiometabolic conditions, and higher use of ototoxic medications. Although these factors are likely to contribute to the elevated risk of hearing loss, the persistence of the association after adjustment suggests that TED may be an independent risk factor. Additional predictors identified included tinnitus, dry eye, and use of aminoglycosides or macrolide antibiotics.\u003c/p\u003e \u003cp\u003eWhile TED is primarily recognized for its ocular and orbital manifestations, the identification of hearing loss, particularly sensorineural subtypes, as a frequent concurrent condition supports its classification as a systemic autoimmune condition with broad physiological impacts. Proposed mechanisms include immune-mediated inflammation, altered cochlear microcirculation, and disruption of neural signaling in the auditory pathway.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e The high prevalence of concurrent conditions among patients with TED, including type 2 diabetes and hypertension which are both independently associated with hearing loss\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e, may compound the overall disease burden through multifactorial pathways.\u003c/p\u003e \u003cp\u003eTogether, these clinical factors translate into meaningful challenges for patients, as the implications of hearing loss for patient well-being are substantial. Hearing loss can exacerbate communication difficulties, social withdrawal, and psychological distress in a population already challenged by visual and systemic symptoms.\u003csup\u003e\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e The findings suggest that a multidisciplinary, cross-specialty approach is necessary to optimize care. Patient education and monitoring may also be valuable, particularly given the potential for under recognition of auditory symptoms and dysfunctions in TED and the multifactorial nature of hearing loss. Awareness of auditory risk in this population, including among young adults and males, as well as informed selection of ototoxic medications, may support timely recognition and intervention, ultimately improving patient outcomes.\u003c/p\u003e \u003cp\u003eAmong its strengths, this study leveraged a large, longitudinal US claims database, enabling precise estimation of incidence, prevalence, and cumulative incidence across age and sex subgroups. Standardization to the 2020 US population enhanced comparability, and adjustment for concurrent conditions and ototoxic medication use strengthened internal validity. Finally, this analysis was conducted before the approval of teprotumumab and therefore provides baseline epidemiologic data that is not influenced by its use.\u003c/p\u003e \u003cp\u003eLimitations include reliance on International Classification of Diseases (ICD) diagnostic codes from insurance claims, which may lead to underreporting or misclassification of hearing loss, particularly in mild or undiagnosed cases. Due to the absence of specific ICD codes for TED, an algorithm was used to identify patients with TED and may be subject to misclassification. The primarily commercially insured population may not fully represent individuals with public insurance or those uninsured. Claims data were missing clinical details such as audiometric measures, TED severity, disease duration, and patient-reported outcomes, limiting characterization of disease impact. The retrospective design prevents determination of causality or temporal sequencing between TED and hearing loss.\u003c/p\u003e \u003cp\u003eIn conclusion, this large population-based study demonstrates that patients with TED face a significantly elevated risk of hearing loss, particularly of the sensorineural subtype, even in young, low-risk populations. These findings support recognition of TED as a systemic autoimmune disease with auditory implications, highlight the need for continued investigation into underlying mechanisms, and suggest patient education and monitoring may help reduce the unrecognized burden of hearing loss in this population.\u003c/p\u003e \u003cp\u003eFuture large-scale prospective studies are warranted to clarify causal pathways between thyroid disease and hearing loss, differentiate subtypes such as sensorineural and conductive, and assess the impact of thyroid-directed therapies (e.g., antithyroid drugs, corticosteroids, teprotumumab) on auditory outcomes. Advancing knowledge in this area is critical to shaping comprehensive care pathways and ultimately improving long-term outcomes for patients with TED.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAlzheimer\u0026rsquo;s disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCharlson Comorbidity Index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003econfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCKD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003echronic kidney disease,COPD,chronic obstructive pulmonary disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGraves\u0026rsquo; disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003egeneral population\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehazard ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInternational Classification of Diseases\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICD-9-CM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInternational Classification of Diseases,Ninth Revision,Clinical Modification\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICD-10-CM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInternational Classification of Diseases,Tenth Revision,Clinical Modification\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einterquartile range\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enumber of patients\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNSAID\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enonsteroidal anti-inflammatory drug\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003estandard deviation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSNHL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003esensorineural hearing loss\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTED\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ethyroid eye disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eUS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eUnited States\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWCG\u0026reg; IRB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e Western Institutional Review Board-Copernicus Group.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003ch2\u003eConsent for publication\u003c/h2\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e\n\u003cp\u003eThe dataset supporting the conclusions of this article is available in the Merative\u0026trade; MarketScan\u0026reg; Research Databases. Restrictions apply to the availability of these data, which were used under license for the current study and are therefore not publicly available. Data may be obtained from the authors upon reasonable request and with permission from Merative.\u003c/p\u003e\n\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003eJAB: Amgen (consultant). VM: Amgen (consultant), Viridian Therapeutics Inc. (consultant), Coppersmith Brockelman Lawyers (consultant), hearX SA (Pty) Ltd (advisory board). JM: Amgen (employment and stock ownership). DC: Amgen (contractor). PF: Amgen (employment and stock ownership). HP: Amgen (employment and stock ownership).\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis work was supported by Amgen Inc., USA.\u0026nbsp;The sponsor participated in the design of the study, conducting the study, interpretation of the data, and review or approval of the manuscript.\u003c/p\u003e\n\u003ch2\u003eAuthors\u0026rsquo; contributions\u003c/h2\u003e\n\u003cp\u003eJAB, VM, JM, DC, PF, and HP contributed to study conceptualization and methodology.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eJM, DC, PF, and HP acquired funding, conducted the investigation, developed the software, performed formal analysis, validation, and visualization, were responsible for project administration, and contributed to writing and review of the manuscript. All authors reviewed and approved the final draft.\u003c/p\u003e\n\u003ch2\u003eAcknowledgments\u003c/h2\u003e\n\u003cp\u003eMedical writing and editorial assistance was provided by Lorena Tonarelli, MSc, of LT Medical \u0026amp; Value Communications Ltd, and funded by Amgen Inc.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003ePrevious presentations\u003c/h2\u003e\n\u003cp\u003eThe authors disclose that part of the work described in this manuscript was previously presented as a poster at the American Academy of Ophthalmology (AAO) Annual Meeting 2025, held October 18-20, 2025, Orlando, FL, USA.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eToro-Tobon D, Stan MN et al. Graves' Disease and the Manifestations of Thyrotoxicosis. In: Feingold KR, Ahmed SF, Anawalt B, Blackman MR, Boyce A, Chrousos G, editors. Endotext. South Dartmouth (MA)2000.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWei Y, Li X, Cui R, Liu J, Wang G. Associations between sensitivity to thyroid hormones and insulin resistance in euthyroid adults with obesity. Front Endocrinol (Lausanne). 2024;15:1366830.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSu T, Gan Y, Ma S, Wu H, Lu S, Zhi M, et al. Graves' disease and the risk of five autoimmune diseases: A Mendelian randomization and colocalization study. Diabetes Metab Syndr. 2024;18(5):103023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSmith TJ, Holt RJ, Fu Q, Qashqai A, Barretto N, Conrad E, et al. Assessment of hearing dysfunction in patients with Graves\u0026rsquo; disease and thyroid eye disease without or with teprotumumab. J Clin Endocrinol Metab. 2025;110(3):811\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShah SS, Patel BC. Thyroid Eye Disease. StatPearls. Treasure Island (FL)2025.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKulbay M, Tanya SM, Tuli N, Dahoud J, Dahoud A, Alsaleh F, et al. A comprehensive review of thyroid eye disease pathogenesis: from immune dysregulations to novel diagnostic and therapeutic approaches. Int J Mol Sci. 2024;25(21):11628.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBerker D, Karabulut H, Isik S, Tutuncu Y, Ozuguz U, Erden G, et al. Evaluation of hearing loss in patients with Graves\u0026rsquo; disease. Endocrine. 2012;41(1):116\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMahafzah M, Mahafza T, Omari H, Al Hawari H. Investigating the possible audiological effects of hypothyroidism. J Phonet Audiol. 2018;4:1.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMahafzah M, Al Hawari H, Momani M, Abbasi N. The prevalence of hearing loss in patients with autoimmune thyroid disease: a prospective study. J Med J. 2018;52(3):109\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTsai Y-T, Chang I-J, Hsu C-M, Yang Y-H, Liu C-Y, Tsai M-S, et al. Association between sudden sensorineural hearing loss and preexisting thyroid diseases: a nationwide case-control study in Taiwan. Int J Environ Res Public Health. 2020;17(3):834.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAthanasopoulos M, Samara P, Athanasopoulos I. Decoding the impact of autoinflammatory/autoimmune diseases on inner ear harmony and hearing loss. Explor Immunol. 2024;4(1):73\u0026ndash;89.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRizk HG, Lee JA, Liu YF, Endriukaitis L, Isaac JL, Bullington WM. Drug-Induced Ototoxicity: A Comprehensive Review and Reference Guide. Pharmacotherapy. 2020;40(12):1265\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLawrence BJ, Jayakody DM, Bennett RJ, Eikelboom RH, Gasson N, Friedland PL. Hearing loss and depression in older adults: a systematic review and meta-analysis. Gerontologist. 2020;60(3):e137\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNordvik \u0026Oslash;, Laugen Heggdal PO, Br\u0026auml;nnstr\u0026ouml;m J, Vassbotn F, Aarstad AK, Aarstad HJ. Generic quality of life in persons with hearing loss: a systematic literature review. BMC Ear Nose Throat Disord. 2018;18(1):1.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBigelow RT, Reed NS, Brewster KK, Huang A, Rebok G, Rutherford BR, et al. Association of hearing loss with psychological distress and utilization of mental health services among adults in the United States. JAMA Netw Open. 2020;3(7):e2010986\u0026ndash;e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShafiepour M, Bamdad Z, Radman M. Prevalence of hearing loss among patients with type 2 diabetes. J Med Life. 2022;15(6):772\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRamage-Morin PL, Banks R, Pineault D, Atrach M, Gilmour H. Hypertension associated with hearing health problems among Canadian adults aged 19 to 79 years. Health Rep. 2021:1209\u0026ndash;367.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDelhez A, Lefebvre P, P\u0026eacute;queux C, Malgrange B, Delacroix L. Auditory function and dysfunction: estrogen makes a difference. Cell Mol Life Sci. 2020;77(4):619\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang Y, Mei P, Zhao Y, et al. Associations Between Occupational Noise Exposure, Aging, and Gender and Hearing Loss: A Cross-Sectional Study in China. Audiol Res. 2025;15(4):91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAzuero A. A note on the magnitude of hazard ratios. Cancer. 2016;122(8):1298\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSmith T, Meyers A, Fu Q, Holt R, Zhu K. 8518. Prevalence of Hearing Dysfunction in Patients with Autoimmune Thyroid Disorders, Thyroid Eye Disease and the General US population: A Claims Database Analysis. J Endocr Soc. 2024;8:A1069.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eToyama K, Mogi M. Hypertension and the development of hearing loss. Hypertens Res. 2022;45(1):172\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLoughrey DG, Kelly ME, Kelley GA, Brennan S, Lawlor BA. Association of age-related hearing loss with cognitive function, cognitive impairment, and dementia: a systematic review and meta-analysis. JAMA Otolaryngol Head Neck Surg. 2018;144(2):115\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-endocrine-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bend","sideBox":"Learn more about [BMC Endocrine Disorders](http://bmcendocrdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bend/default.aspx","title":"BMC Endocrine Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Thyroid eye disease, Graves’ disease, hearing loss, sensorineural hearing loss","lastPublishedDoi":"10.21203/rs.3.rs-8801141/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8801141/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eLarge-scale studies characterizing hearing loss among patients with Graves disease (GD) and thyroid eye disease (TED) in the United States are lacking. This study aimed to quantify hearing loss incidence, prevalence, and risk in this population.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eRetrospective study of Merative\u0026trade; MarketScan\u0026reg; Research Databases (2014\u0026ndash;2019) data including individuals aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years with TED (\u0026ge;\u0026thinsp;1 GD diagnosis and \u0026ge;\u0026thinsp;1 eye sign/symptom within 12 months), GD (\u0026ge;\u0026thinsp;2 outpatient [\u0026ge;\u0026thinsp;30 days apart]/\u0026ge;1 inpatient GD diagnoses), or in the general population (GP). Index date was the latter of first GD diagnosis or eye sign/symptom for the TED cohort, the first GD diagnosis for the GD cohort, and the first eligible claim for the GP (baseline: 12 months pre-index; follow-up: from index until hearing loss, disenrollment, death, or data end). Cox models estimated unadjusted/adjusted hazard ratios (HRs) controlling for patient characteristics; time-to-event outcomes were described using Kaplan-Meier methods. Outcomes included incidence, cumulative incidence, prevalence, and HR for hearing loss (identified by ICD-10-CM codes as a composite of conductive hearing loss, sensorineural hearing loss [SNHL], mixed conductive and SNHL, age-related hearing loss). Outcomes were standardized to the 2020 US population by age and sex.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOverall, 20,493,563 (TED: 38,723; GD: 171,831; GP: 20,283,009) patients were included. Measures of hearing loss were highest in TED (incidence: 142.2 per 10,000 person-years; cumulative incidence: 2.8%; prevalence: 4.6%) versus GD (92.0; 2.0%; 3.0%) and GP (67.6; 1.6%; 2.2%). SNHL was the most frequent subtype. TED showed increased unadjusted risk versus GP (HR 2.6; 95% confidence interval [CI], 2.5\u0026ndash;2.8), persisting after adjustment (HR 1.6; 95% CI, 1.5\u0026ndash;1.7) with a 60% higher risk of hearing loss. Cumulative incidence increased with age, with patients with TED having higher rates than those with GD or in the GP (18\u0026ndash;35 years: 0.8%, 0.4%, and 0.3% for TED, GD, and GP; \u0026ge;86 years: 11.5%, 8.9%, and 7.3%). Cumulative incidence was higher among males than females (TED: 4.3% vs. 3.0%; GD: 2.5% vs. 2.0%; GP: 1.6% vs. 1.3%).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eTED and GD are independently associated with high rates of hearing loss diagnosis, supporting their recognition as systemic autoimmune diseases with auditory implications.\u003c/p\u003e","manuscriptTitle":"Epidemiology and risk factors of hearing loss in thyroid eye disease in the United States: A retrospective study of MarketScan® data","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-10 17:16:24","doi":"10.21203/rs.3.rs-8801141/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"13547540104987427496992694170147226169","date":"2026-03-17T05:28:31+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-05T11:54:59+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-09T10:48:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-06T22:14:13+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-06T22:13:40+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Endocrine Disorders","date":"2026-02-05T22:45:35+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-endocrine-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bend","sideBox":"Learn more about [BMC Endocrine Disorders](http://bmcendocrdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bend/default.aspx","title":"BMC Endocrine Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"af469124-1d7e-4313-89b9-0d7b37e3fe37","owner":[],"postedDate":"March 10th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-10T17:16:24+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-10 17:16:24","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8801141","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8801141","identity":"rs-8801141","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}