Challenges in Identifying Noise-Induced Hearing Loss Phenotype for Genetic Analysis

Noise-Induced Hearing Loss (NIHL) presents complex challenges in genetic association analysis due to factors like gene-environment interactions and varying susceptibility among individuals. Phenotyping plays a crucial role in gene mapping accuracy by defining specific traits of the condition. Early efforts focused on audiometric thresholds, while recent strategies involve identifying notches in hearing sensitivity frequencies. These advancements aim to enhance the precision and sensitivity of gene-environment studies for NIHL.

• NIHL
• Genetic Analysis
• Phenotyping
• Hearing Loss
• Gene-Environment

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1. 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.

2. Disclosure We have no relevant financial or nonfinancial relationships to disclose

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

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

5. 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

6. 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)

7. 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

8. Audiometric Notch Phillips et al. (2015)

9. 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)

10. 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)

11. 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

12. Computer-Simulated Audiograms Step 1: Step 2: Truncated Normal Distribution Mean= 0 SD = 7.5 Simulate 3000 values 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)

13. 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)

14. 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%

15. Audiometric Notch (NHANES:2005-10)

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

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

18. 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

19. 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

20. 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.