Distortion Product Otoacoustic Emissions in Screening for Early Stages of High-frequency Hearing Loss in Adolescents.

Objective: Adolescents may be at risk of noise-induced hearing loss due to recreational sound. The aim of this study was to examine the role of distortion product otoacoustic emissions (DPOAEs) in screening for early stages of high-frequency loss such as can be observed in noise-induced hearing loss. Setting and design: This cross-sectional study was embedded within Generation R, an ongoing prospective birth cohort study in Rotterdam, The Netherlands. Data were collected from April 2016 to September 2019.
Methods: A total of 3456 adolescents with a mean age of 13 years and 8 months old (standard deviation ± 5 months) were included. Pure-tone thresholds were measured in a sound-treated booth. DPOAEs were recorded using an ILO V6 analyzer with primary levels of 65/55 dB SPL and frequency ratio f2/f1 of 1.22. Subjects had normal middle ear function at the time of assessment, based on tympanometry results.
Results: Measurements in 6065 ears showed that DPOAE levels tend to decrease with increasing pure-tone thresholds. However, the intersubject variability of DPOAE levels in ears with the same threshold was large. DPOAE levels could reasonably identify early stages of high-frequency hearing loss.
Conclusion: The findings of present study indicate that DPOAE measurements can potentially be used for adolescents hearing screening in the high frequencies. Future research is needed to optimize test performance.

INTRODUCTION

There is widespread concern that the prevalence of acquired hearing loss in adolescents is rising, due to an increase in recreational noise exposure.[123] Adolescents may be unaware or oblivious to the potential harm caused by excessive noise exposure.[45] Noise can cause a broad set of metabolic and structural changes in the cochlea, changes that can eventually lead to irreversible hearing loss.[6] By identifying hearing deficits in an early stage, progression can possibly be prevented and adverse effects minimized.[7] Thereby, the individual and global burden of hearing loss can be reduced.

Distortion product otoacoustic emissions (DPOAEs) are widely used to study cochlear function. They are a by-product of the cochlear amplifier, which can be recorded in the ear canal in response to two closely spaced stimulus tones.[8] DPOAEs reflect the integrity of the outer hair cells, essential for hearing sensitivity, and frequency selectivity.[9] The presence of DPOAEs is generally associated with normal hearing, and is reduced or absent in individuals with hearing loss.[101112] It is this close relationship between DPOAEs and cochlear status that has driven the clinical application of DPOAEs for screening purposes. Moreover, DPOAEs have the advantages of being fast and easy to obtain, and require minimal behavioral response.

The DPOAEs are primary in use in universal newborn hearing screening programs, with the aim of detecting congenital hearing loss as soon as possible, and additionally in diagnostic settings. In adults, DPOAEs have been shown to accurately identify hearing loss in the mid and high frequencies, particularly for hearing losses between 20 and 30 dB hearing level (HL).[1113] Although many studies have examined the performance of DPOAEs as screening tool in infants and adults, large studies in adolescents are not available. As reduced emission levels have been reported with increasing age,[1415] the results found in the adult population cannot simply be extrapolated to other age groups. To bridge the knowledge gap between infants and adults, we examined the test performance of DPOAEs specific to the adolescent population. We aimed to examine the relationship between pure-tone thresholds and DPOAE levels in a large population-based cohort of 13-year adolescents. The focus of the study was on the ability of DPOAEs to detect early stages of high-frequency loss such as can be observed in noise-induced hearing loss.

METHODS

Study design and population

This study was embedded in the Generation R Study, an ongoing multiethnic population-based prospective cohort from fetal life onward in Rotterdam, The Netherlands. The study was approved by the Medical Ethics Committee of Erasmus Medical Center and written informed consent was obtained from both parents of all participating children. Details on study design, response rate, and (loss to) follow-up have been published previously.[16]

Adolescents aged 12 to 17 years were invited to the research center in the Erasmus Medical Center − Sophia Children’s Hospital to undergo hearing assessment. Subjects were eligible for inclusion if they completed DPOAE assessment and pure-tone audiometry. Tympanometry was performed to assess middle ear function. Subjects were excluded if they had an abnormal tympanogram, as described below. Data were collected from April 2016 to September 2019.

Measurements

Tympanometry

All subjects had middle ear function assessed for both ears, unless there was a contraindication such as excessive wax, otorrhea, acute otitis media, or recent ear surgery. Assessment of middle-ear function is of importance, as the transmission properties of the middle ear directly influence DPOAE characteristics.[17] Tympanometry was conducted using an Interacoustics AT235h middle-ear analyzer with a 226-Hz probe tone. Ears with an ear canal volume smaller than 0.3 mL were excluded to avoid ear canal collapse or occlusive cerumen influencing the results. A compliance below 0.25 mL and/or middle ear pressure below −100 da Pascal were considered as abnormal as it could present external or middle ear pathology.[18] Ears who had abnormal or missing tympanometry were excluded from the analyses.

Distortion product otoacoustic emissions

The DPOAEs were measured using an ILO V6 Analyzer and ILO probes with disposable tips. Calibration and a functional check of the probe were performed on a weekly basis. Adequacy of probe fit was checked before the start of data acquisition. DPOAEs were measured in response to two primary tones, presented simultaneously, at frequencies f1 and f2 and levels L1 and L2. The ratio of the two frequencies (f2/f1) was set at 1.22 as this ratio tends to produce the largest distortion products.[19] The stimuli levels were held constant at L1 = 65 dB sound pressure level (SPL) and L2 = 55 dB SPL.[20] Cubic distortion products (2 f1–f2) were measured at four points per octave, and the results were analyzed at the f2 frequencies 814 to 8000 Hz. Sampling at each test frequency continued until the noise floor was below −20 dB SPL. After 90 seconds, testing automatically stopped. Distortion products were plotted on a DP-Gram with the f2 frequency on the horizontal axis and the DPOAE amplitude of the 2 f1 − f2 distortion product (DPOAE level) on the vertical axis. The DPOAE level at each f2 frequency was chosen as the basic parameter to be correlated with the pure-tone threshold as it is a direct measure of cochlear function. The signal-to-noise ratio, on the other hand, is a composite measure that depends not only on the status of the cochlea but also on the measurement conditions, represented by the noise floor present during the recording.[21]

To ensure noise levels were sufficiently low that even small emissions could be detected, a threshold criterion for the noise floor was used. This threshold criterion was determined from measurements in the cohort, namely two standard deviations above the average noise floor.[22] The average noise floor across the frequency range 814 to 8000 kHz was calculated for each ear. When this value exceeded the cohort’s average noise floor plus two standard deviations, ears were excluded. Other reasons for exclusion were inadequate technical conditions for recording and research assistants, indicating uncertainty regarding correct insertion of the probes, that is, mistakenly changing the right and left ear probes.

Pure-tone audiometry

Pure-tone audiometry was performed in a sound-treated booth meeting the maximum permissible ambient sound pressure levels of ISO standard 8253-1. Hearing thresholds were assessed using a clinical audiometer (Decos audiology workstation; version 210.2.6 with AudioNigma interface) and TDH-39P headphones with MX-41/AR ear cushions, calibrated every 12 months. Air conduction pure-tone thresholds were obtained at the frequencies 0.5, 1, 2, 3, 4, 6, and 8 kHz. Due to time constraints, no bone conduction thresholds were measured. Testing began at 20 dB HL. The level was reduced by 10 dB HL or increased by 5 dB HL according to the presence or absence of a response. The actual threshold was set after two out of three responses were consistent. The right and left ears were randomly tested first.

Statistical analyses

Scatterplots were created to examine the relationship between pure-tone thresholds and DPOAE levels at the individual frequencies 3 to 8 kHz, the frequencies mainly affected by noise exposure.[23] As the audiometric frequencies and f2 frequencies did not always correspond, we interpolated the DPOAE level at 3000 Hz from those at 2828 and 3364 Hz, and at 6000 Hz from 5657 and 6757 Hz. The frequencies between 3 and 8 kHz were also averaged, as Sisto et al. (2007) demonstrated that averaging over sufficiently large bandwidth is necessary to obtain a good correlation between DPOAE levels and pure-tone thresholds.[24]

A receiver-operating characteristic (ROC) curve was constructed to evaluate the diagnostic utility of DPOAEs to identify ears with high-frequency hearing loss such as can be observed in noise-induced hearing loss.[23] In a ROC curve, the true positive rate (proportion of abnormal hearing ears correctly classified as abnormal) is plotted against the false-positive rate (proportion of normal hearing ears incorrectly classified as abnormal). The mean DPOAE level across the frequencies 2828 to 8000 Hz was used to detect high-frequency hearing loss as measured by pure-tone audiometry. High-frequency hearing loss was defined as (1) a threshold of 15 dB HL or less at 0.5 and 1 kHz, and (2) an average threshold of 3, 4, 6, and 8 kHz >15 dB HL.[25] The area under the curve (AUC) was used as overall measure of test performance. Statistical analyses were performed using SPSS version 24.0 [IBM SPSS Statistics software (version 24.0 for Windows)] for Windows software (SPSS Inc) and R version 3.6.1.

RESULTS

Between April 2016 and September 2019, 4929 adolescents visited the research center. DPOAEs and pure-tone thresholds were measured in 7652 ears, of whom 6248 (81.7%) had normal middle ear function based on tympanometry results. Fifty-two ears (0.8%) were excluded due to inadequate technical conditions for recording or incorrect insertion of the probes, and 131 ears (2.1%) due to an average noise floor above the threshold criterion. A total of 3456 subjects and 6065 ears were included. There was an equal distribution between right and left ears. Subjects were on an average 13 years and 8 months old (standard deviation ±5 months), and 1773 (51.3%) were girls.

Pure-tone audiometry

The cohort’s average pure-tone thresholds of right and left ears are demonstrated in Figure 1. The lowest (best) thresholds were observed at 1 kHz, and highest (poorest) thresholds at 8 kHz.

Figure 1

The cohort’s average pure-tone thresholds (dB HL) of the right and left ears. The error bars represent ±1 standard deviation.

Distortion product otoacoustic emissions

The average DPOAE level varied from ‒7.4 to 7.9 dB SPL across the frequency range 841 to 8000 Hz, with a peak observed at 1682 and 4757 Hz [Figure 2]. There was a high degree of variability in DPOAE levels, with standard deviation values ranging from 9.6 to 12.8 dB SPL. The average noise floor ranged from −13.2 to −1.3 dB SPL, with a standard deviation of 2.5 to 5.5 dB SPL. When ears with a pure-tone threshold >15 dB HL at any of the frequencies were excluded, the average DPOAE level varied from −5.9 to 7.9 dB SPL.

Figure 2

The cohort’s average DPOAE level and noise floor as a function of f2 frequency. The shaded areas represent ±1 standard deviation. DPOAE, distortion product otoacoustic emission.

Pure-tone audiometry and distortion product otoacoustic emissions

Figure 3 shows the relationship between pure-tone thresholds and DPOAE levels at the frequencies 3, 4, 6, and 8 kHz, and the average of these frequencies. There were many data points with similar values, thereby plotted on top of each other. Boxplots of the DPOAE level for different groups of ears based on the pure-tone threshold are presented in Supplementary Figure 5. In general, DPOAE levels tend to decrease with increasing hearing threshold. However, the vertical dispersion of the data was large.

Figure 3

Scatterplots of DPOAE level (dB SPL) as a function of pure-tone threshold (dB HL). Ears with a signal-to-noise ratio (SNR) ≥ 0 dB were presented black, and ears with a SNR < 0 dB in gray. DPOAE, distortion product otoacoustic emission.

Figure 5

(Supplementary) Boxplots of the DPOAE level for different groups of ears, based on the pure-tone threshold at the frequencies 3, 4, 6, and 8 kHz, and the average of these frequencies. DPOAE, distortion product otoacoustic emission.

A ROC curve was constructed to evaluate the extent to which ears with high-frequency hearing loss could be distinguished based on the DPOAE level averaged across the frequencies 2828 to 8000 Hz, as demonstrated in Figure 4. A total of 251 (4.1%) ears fulfilled the criteria of high-frequency hearing loss. The test performance was acceptable, with an AUC of 0.747. Table 1 displays the sensitivity and specificity at various cutoff points of DPOAE levels for detecting high-frequency hearing loss. In Supplementary Table 2, the accuracy with which DPOAE levels can identify ears with high-frequency hearing loss when using other definitions of high-frequency hearing loss are presented.

Figure 4

Receiver-operator characteristic curve for the presence of high-frequency hearing loss. The area under the curve is the graph. AUC, area under the curve.

Table 1

Sensitivity and specificity of DPOAEs for detecting high frequency hearing loss at different cutoff points

DPOAE level 2828–8000 Hz (dB SPL)	Sensitivity	Specificity
−20	0.13	0.96
−15	0.28	0.93
−10	0.38	0.88
−5	0.59	0.80
0	0.74	0.65
5	0.88	0.41
10	0.97	0.15

DPOAE, distortion product otoacoustic emissions.

Table 2

(Supplementary) The accuracy with which distortion product otoacoustic emission levels can identify ears with high-frequency hearing loss using different criteria of high-frequency hearing loss

Definition of high-frequency hearing loss*	Number of ears (%)	AUC
A threshold of <15 dB HL at 0.5 and 1 kHz, and an average threshold at the frequencies
3, 4, 6, and 8 kHz > 15 dB	251 (4.1)	0.747
3, 4, 6, and 8 kHz > 20 dB	54 (0.9)	0.852
3, 4, 6, and 8 kHz > 25 dB	18 (0.3)	0.824
4, 6, and 8 kHz > 15 dB	377 (6.2)	0.737
4, 6, and 8 kHz > 20 dB	96 (1.6)	0.819
4, 6, and 8 kHz > 25 dB	32 (0.5)	0.853

AUC, area under the curve. *Significance.

DISCUSSION

To our knowledge, this is the largest study to describe pure-tone thresholds and DPOAE levels in a population-based cohort of adolescents today. Several studies have reported normative data for DPOAEs in a smaller cohort of adolescents of the same age.[15262728] In these studies, including 31 to 229 subjects, higher DPOAE levels were found (5–15 dB SPL). A possible explanation is that the f2 frequency range differed, with no measurements at 814 and 8000 Hz in the previously described studies. The minimum DPOAE level of −7.4 dB SPL reported in this study was found at 8000 Hz. Despite the differences in level of emissions, the general pattern of the DP-gram was similar. The peak in DPOAE level around 1500 and 4500 Hz was observed by many other researchers, both in pediatric and adult populations.[1527282930]

When examining the relationship between DPOAEs and pure-tone thresholds, we found that DPOAE levels tend to decrease with increasing hearing level. However, there was a large intersubject variability of DPOAE levels in ears with the same threshold. Some of the variability may be attributed to the so-called fine structure; that is, a pattern of peaks and valleys in the 2 f1-f2 DPOAE amplitude.[313233] This fine structure is supposed to be the consequence of physiologic inferences between two difference sources of the cochlea generating the DPOAE response.[34] Differences in fine structure, either in frequency location or magnitude, may cause variability in normal DPOAE responses. Middle-ear transmission characteristics may also explain part of variability observed in DPOAEs among normal hearing ears.

There is no consensus on the role of DPOAEs in the screening for noise-induced hearing loss.[24353637] In this study, we observed that DPOAEs could reasonably identify high-frequency hearing loss such as can be observed in noise-induced hearing loss. Whereas previous research demonstrated that DPOAEs are most effective for detecting hearing losses between 20 and 30 dB HL, the focus of present study was on identifing early stages of hearing loss.[1113] It is important to keep in mind that the number of ears with high-frequency hearing loss was relatively low due to young age of our study population. Moreover, we assumed any high-frequency hearing loss to be associated with excessive noise exposure. However, high-frequency hearing loss could also result from other causes such as hereditory factors and ototoxic drugs. In this cross-sectional study, no inferences can be made on the cause of detected hearing losses.

Evaluating hearing status with a single DPOAE test is difficult considering the large dispersion of DPOAE levels within a population. However, there might be potential for DPOAEs in monitoring hearing function, since then the change within a single subject is of importance, and not the value itself. Several investigators have even suggested that DPOAEs are more sensitive in detecting subclinical cochlear damage compared to pure-tone audiometry. This evidence is mainly predicated upon the observation of lower emission levels in noise-exposed subjects compared to nonexposed subjects, whereas pure-tone thresholds were within normal limits.[38394041] Although this implicates that DPOAE levels decrease before hearing thresholds increase, most of these findings were based on cross-sectional studies. For an actual predictive value, longitudinal studies are required.

Strengths and limitations

The current study was conducted as part of the Generation R Study. The strengths include the prospective design and large sample size. Hearing was assessed by dedicated research assistants with a small variance, resulting in a relatively homogenous setting. A limitation of the study is that no otoscopic examination and bone-conduction audiometry were performed due to time constraints, with hearing assessment being just one of the multiple measurements at the research center. Tympanometry was performed to identify middle ear pathology. Although tympanometry is a fairly sensitive and reliable technique in the diagnosis of middle-ear dysfunction,[42] it is possible that middle-ear pathology was not detected by tympanometry and conductive hearing loss was incorrectly classified as sensorineural loss. Furthermore, to this point, we have assumed that any error is associated with DPOAE testing, as pure-tone audiometry is considered the gold standard. However, it is important to keep in mind that pure-tone audiometry has a test–retest variability of about 5 dB HL.[43] It could be that normal hearing ears were incorrectly classified as hearing impaired, and the other way around. As it has long been known that the outer hair cells in the cochlea are vulnerable to excessive noise more recently, animal studies have demonstrated that noise can also damage the synapses between the inner hair cells and auditory nerve fibers, which is called cochlear synaptopathy.[4445] As cochlear synaptopathy can occur without affecting pure-tone thresholds and DPOAE level,[46] it was outside the scope of this study.

Future research

DPOAEs and pure-tone thresholds within the Generation R study will be repeatedly measured, and longitudinal data that will become available in the future. We aim to investigate whether (i) DPOAE levels change with age, (ii) a decline in DPOAE levels can be observed with a deterioration of hearing, (iii) subjects with low emissions but normal hearing at baseline have decreased thresholds during follow-up, and (iv) the association between DPOAE levels and noise exposure.

CONCLUSIONS

Although a consistent relationship between pure-tone thresholds and DPOAE levels was found, the intersubject variability of DPOAE levels in ears with the same threshold was large. We observed that DPOAEs can reasonably identify slight to mild levels of high-frequency hearing loss such as can be observed in noise-induced hearing loss. Future research is needed to improve test performance, and determine the role of DPOAEs in predicting and monitoring hearing loss in this age group.

Financial support and sponsorship

The general design of Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam, ZonMw, The Netherlands Organization for Scientific Research (NWO), and the Ministry of Health, Welfare and Sport. The researchers are independent from the funders. The study sponsors had no role in the study design, data analysis, interpretation of data, or writing of this report.

Conflicts of interest

There are no conflicts of interest.