Clinical Challenges in Identifying Noise-Induced Hearing Loss (NIHL) Phenotype for Genetic Association Analysis Presenter Ishan Bhatt, Ph.D., CCC-A Coauthors/Contributors O’neil Guthrie, Ph.D., CCC-A Michael Skelton, Ph.D., CCC-A, FAAA Viacheslav Fofanov, Ph.D. Srinivas Kosaraju, Ph.D. Omar Badreddin, Ph.D.

Disclosure We have no relevant financial or nonfinancial relationships to disclose

Complex Disorders Complex disorders: multiple factorial disorders Their causes: multiple genes in combination with lifestyle and environmental factors No clear-cut pattern of inheritance Family Clustering

NIHL is a Complex Disease Some individuals are more susceptible to noise than others Challenging to estimate a person's risk of inheriting or passing on NIHL causing genes Gene Environment Gene-environment interaction

Importance of Phenotyping NIHL Success of gene mapping lies on the ability to define the target phenotype (i.e. trait of a disease) with accuracy and precision A well-defined phenotype can improve sensitivity and specificity of gene-environment association studies

Early Efforts: Phenotyping NIHL Definition: Absolute audiometric thresholds at high frequencies (3 to 8 kHz) Industrial population Confounding variables (Sliwinska-Kowalska & Pawelczyk, 2013; Konings et al., 2006)

Recent Efforts: Phenotyping NIHL Notch: A drop in hearing sensitivity at 4 to 6 kHz of at least 15 dB from the self-referenced previous best threshold in a linear progression of frequencies, with a recovery of at least 5 dB after the notch NIHL phenotype = Bilateral notches College-aged student musicians for better control over confounding variables

Audiometric Notch Phillips et al. (2015)

Is NIHL Overestimated? Almost 45% of college-aged musicians showed an audiometric notch at least in one ear. Almost 12% showed bilateral notches (Phillip et al., 2010) Most notches occurred at 6000 Hz A previous study argued that “sensitive” notch definition especially including unweighted 6000 Hz threshold (used by Niskar et al, 2001) may lead to high false positives (Schlauch & Carney, 2011)

Aims of the Study To study the prevalence and associated factors of the audiometric notch in US youth (12-19 years) To examine the possibility of overestimating the audiometric notch defined as the NIHL phenotype in our previous study (Phillips et al, 2015)

Methods Demographic and audiometric databases from NHANCES (2005-10) Participants aged 12-19 years; Bilateral otoscopy: No abnormality detected Tympanogram: compliance value from 0.2 to 1.8 cc, and MEP value from -50 to 25 dapa in both ears were considered for the study Total participants for the analysis: 2348

Computer-Simulated Audiograms Step 1: Truncated Normal Distribution Mean= 0 SD = 7.5 Simulate 3000 values Step 2: “Actual” Audiogram Simulation Selected value was used as person’s “actual threshold” Selected “actual threshold” value for this example is 0 dB HL -10 dB HL 5 dB added in the selected value to derive “actual threshold” at 6000 and 8000 Hz (Schlauch & Carney, 2011)

Computer-Simulated Audiograms Step 3: Sensory Threshold Simulation “sensory thresholds” were simulated by selecting a random value from the normal curve Step 4: Rounding Sensory thresholds were rounded to nearest 5 dB value Threshold lower than -10 dB HL were rounded to -10 dB HL Mean= Actual Threshold SD = 5 (Schlauch & Carney, 2011)

Prevalence of bilateral in a general population Aim 1: Result Prevalence of bilateral notch was 16.6% in a general population aged 12-19 years Aim 2: Result Estimated false positive rate: At least 5.5%

Audiometric Notch (NHANES:2005-10)

Almost 93% simulated notched audiograms showed 15-20 dB of notch depth

Audiometric Notch: Associated Factors Associated Variables Unilateral Notch (Odds Ratio) Males < Females 0.753 (0.618-0.918) African Americans < European Americans 0.700 (0.538-0.911) 14-15 years > 18-19 years Associated Variables Bilateral Notch (Odds Ratio) Males < Females 0.585 (0.450-0.761) African Americans < European Americans 0.537 (0.376-0.767) Noisy Job > No noisy job 1.836 (1.097-3.074) Music exposure, firearm exposure, smoking, family income and tinnitus showed no association with the audiometric notch

Discussion Almost 42% of the participants showed an audiometric notch without reporting a history of a noisy job, music exposure, firearm noise exposure and acoustic exposure before audiometry. Participants aged 12-13 years showed 40% prevalence of unilateral notch and 13.5% prevalence of bilateral notch Prevalence of audiometric notch in US youth (12-19 years) was higher than its prevalence in college-aged musicians

Discussion(continue) Phillips et al (2010 & 2015) and NHANES used TDH 50 type supra-aural transducers Supra-aural transducers show poor test-retest reliability at high frequencies especially around 6000 Hz (Mello et al, 2015) Standing waves in the ear canal is a candidate mechanism for high false positive rates observed in the NHANES data

References Gerhardt, K. J., Rodriguez, G. P., Hepler, E. L. & Moul. 1987. Ear canal volume and variability in the patterns of temporary threshold shifts. Ear and hearing. 8(6), 316-321. Konings, A., Van Laer, L. & Van Camp, G. 2009. Genetic studies on noise-induced hearing loss: a review. Ear and hearing, 30(2), 151-159. Mello, L., da Silva, Gil, D. 2015. Test-retest variability in the pure tone audiometry: comparison between two transducers. Audiol Commun Res, 20(3), 239-245. Niskar, A.S., Kieszak, S.M., Holmes, A.E., Esteban, E., Rubin, C. & Brody, D.J. 2001. Estimated prevalence of noise-induced hearing threshold shifts among children 6 to 19 years of age: the Third National Health and Nutrition Examination Survey, 1988-1994, United States. Pediatrics, 108(1), 40-43. Phillips S.L., Henrich V.C. & Mace S.T. 2010. Prevalence of noise-induced hearing loss in student musicians. Int J Audiol, 49, 309–31 Phillips, S.L., Richter, S.J., Teglas, S.L., Bhatt, I.S. et al. (2015). Feasibility of a bilateral 4000-6000 Hz notch as a phenotype for genetic association analysis. IJA, 54(10), 645-652. Schlauch, R. & Carney, E. (2011). Are False-Positive Rates Leading to an Overestimation of Noise-Induced Hearing Loss? JSLHR, 54, 679-692. Sliwinska-Kowalska, M. & Pawelczyk, M. 2013. Contribution of genetic factors to noise-induced hearing loss: a human studies review. Mutation research, 752(1), 61-65.