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
No clear-cut pattern of inheritance
Family Clustering

4. 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

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 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:
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)

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. Prevalence of bilateral in a general population
Aim 1: Result
Prevalence of bilateral
notch was 16.6%
in a general population
aged 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)
Males < Females
0.753
( )
African Americans < European Americans
0.700
( )
14-15 years > years
Associated Variables
Bilateral Notch
(Odds Ratio)
Males < Females
0.585
( )
African Americans < European Americans
0.537
( )
Noisy Job > No noisy job
1.836
( )
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 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 Ear canal volume and variability in the patterns of temporary threshold shifts. Ear and hearing. 8(6),
Konings, A., Van Laer, L. & Van Camp, G Genetic studies on noise-induced hearing loss: a review. Ear and hearing, 30(2),
Mello, L., da Silva, Gil, D Test-retest variability in the pure tone audiometry: comparison between two transducers. Audiol Commun Res, 20(3),
Niskar, A.S., Kieszak, S.M., Holmes, A.E., Esteban, E., Rubin, C. & Brody, D.J Estimated prevalence of noise-induced hearing threshold shifts among children 6 to 19 years of age: the Third National Health and Nutrition Examination Survey, , United States. Pediatrics, 108(1),
Phillips S.L., Henrich V.C. & Mace S.T 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 Hz notch as a phenotype for genetic association analysis. IJA, 54(10),
Schlauch, R. & Carney, E. (2011). Are False-Positive Rates Leading to an Overestimation of Noise-Induced Hearing Loss? JSLHR, 54,
Sliwinska-Kowalska, M. & Pawelczyk, M Contribution of genetic factors to noise-induced hearing loss: a human studies review. Mutation research, 752(1),