Long-Term Variability of Distortion-Product Otoacoustic Emissions in Infants and Children and Its Relation to Pediatric Ototoxicity Monitoring

Abstract

Objective: Distortion-product otoacoustic emissions (DPOAEs) provide a rapid, noninvasive measure of outer hair cell damage associated with chemotherapy and are a key component of pediatric ototoxicity monitoring. Serial monitoring of DPOAE levels in reference to baseline measures is one method for detecting ototoxic damage. Interpreting DPOAE findings in this context requires that test-retest differences be considered in relation to normal variability, data which are lacking in children. This study sought to (1) characterize normal test-retest variability in DPOAE level over the long time periods reflective of pediatric chemotherapy regimens for a variety of childhood ages and f2 primary frequencies using common clinical instrumentation and stimulus parameters; (2) develop level-shift reference intervals; and (3) account for any age-related change in DPOAE level or measurement error that may occur as the auditory system undergoes maturational change early in life.

Design: Serial DPOAE measurements were obtained in 38 healthy children (25 females and 13 males) with normal hearing and ranging in age from one month to 10 years at the initial (baseline) visit. On average, children were tested 5.2 times over an observation period of 6.5 months. Data were collected in the form of DP grams, in which DPOAE level was measured for f2 ranging from 1.4 to 10 kHz, using a fixed f2/f1 ratio of 1.22 and stimulus level of 65/55 dB SPL for L1/L2. Age effects on DPOAE level and measurement error were estimated using Bayesian regression of the longitudinal data. The raw and model-based distribution of DPOAE test-retest differences were characterized using means and standard error of the measurement for several ages and f2's.

Results: DPOAE test-retest differences for the children in this study are at the high end of those previously observed in adults, as reflected in the associated shift reference intervals. Further, although we observe substantial child-specific variation in DPOAE level, the pattern of age-related changes is highly consistent across children. Across a wide range of f2's, DPOAE level decreases by 3 to 4 dB from 1 to 13 months of age followed by a more gradual decline of <1 dB/year. An f2 of 6 kHz shows the smallest decrease during the early rapid maturation period. DPOAE measurement error is fairly constant with age. It is 3 to 4 dB at most f2's and is greater (indicating poorer reliability) at 1.5, 8, and 10 kHz.

Conclusions: DPOAE level decreases with childhood age, with the greatest changes observed in the first year of life. Maturational effects during infancy and greater measurement error at very low and high f2's affect test-retest variability in children. An f2 of 6 kHz shows minimal maturation and measurement error, suggesting it may be an optimal sentinel frequency for ototoxicity monitoring in pediatric patients. Once validated with locally developed normative data, reference intervals provided herein could be used to determine screen fail criteria for serial monitoring using DPOAEs. Employing state-of-the-art calibration techniques might reduce variability, allowing for more sensitive screen fail criteria.

Figures

Figure 1.. Baseline DP-grams from a cohort of healthy infants and children show substantial variation in DPOAE level.

DPOAE level is plotted by f2 frequency to construct DP-grams using data from the initial (Baseline) visit. Solid lines show DPOAE level; Dashed lines show the level of the noise. Thin lines show data from individual participants; thick line shows the sample means. The variation in DPOAE level across individuals is greatest at the low and high f2 frequency extremes. Note that for a DPOAE recording to be included in the analysis, the signal to noise ratio (SNR) had to be at least 6 dB and amplitude had to be at least −10 dB SPL.

Figure 2.. Test-retest variability is greater in children than previously reported for adults.

The DPOAE level shift relative to baseline is given in dB as a function of test-retest interval for participants grouped by age (columns) at a range of f2 frequencies (rows). Within a panel, thin black lines represent the DPOAE level shift in each ear and the thick red line is a loess smooth fit to the group data. The vertical distance between the red line and the horizontal line indicating zero change can be used to appreciate the magnitude of mean shift. For comparison, the gray box in each panel at f2~2, 4, and 6 kHz, indicates the 90% shift reference interval obtained in a meta-analysis of published data from adults for which test-retest intervals vary from

Figure 3.. Model results showing population average maturational trajectories for DPOAE level at each f2 frequency.

Each panel is for a separate f2. Within a panel, the white line is the posterior median, thin error bars represent the corresponding 90% Bayesian confidence interval while thick error bars show the posterior inter-quartile range. The model results overlay the observed data measured longitudinally in each participant (thin lines). Results indicate that aging in childhood is associated with a reduction in DPOAE level and that this maturational effect, evident by the slope of the white line, tends to be greatest during the first year of life.

Figure 4.. Maturational effects on DPOAE level are evident for a wide range of f2 frequencies, and are less pronounced in childhood than infancy.

Plot shows the median of the posterior distribution of the mean difference in estimated DPOAE level taken between specific ages indicated as points along the thick black line from Fig. 4. Panel A shows the contrast between 1 and 13 months; Panel B shows the contrast between 36 and 48 months of life. In both panels, results are plotted by f2. The thick and thin portions of the error bars indicate the corresponding 25th – 75th and 5th – 95th percentile ranges, respectively. The estimated maturational change during the first year of life is a 2–5 dB decrease in DPOAE level at most f2’s, with no change at 6 and 7 kHz. Panel B indicates less maturational change (1 dB/year) from 36 to 48 months of age and greater certainty in the estimate.

Figure 5.. Modeled measurement error trajectories for DPOAE level recordings show substantial variation with f2 frequency but no consistent age effect.

Each panel is for a separate f2. Within a panel, the thick line is the fitted mean and the shaded area represents the corresponding 95% Bayesian confidence interval. Measurement error is an estimate of reliability similar to an immediate absolute test-retest difference. Larger error is indicative of poorer reliability. Measurement error is typically within 3–4 dB except at the low and high f2 frequency extremes, which are associated with poorer reliability, but pronounced age effects are not evident.

Figure 6.. Model-based average absolute difference between children in DPOAE-level decrement per year of life.

The average absolute difference in the age effect on DPOAE level between children given by f2. Units are dB SPL per year of life. The small average absolute difference in the age effect on DPOAE level between children in the sample indicates a consistent maturational effect at most f2 frequencies. The estimated age effect is variable at an f2 of 1.5 kHz, but is otherwise highly consistent across children.

Figure 7.. Model-based 90% shift reference limits for DPOAE level by observation interval compared for a variety of f2 frequencies and ages.

The 90% shift reference limits corresponding to a given age are represented by the shaded region, with solid or dashed lines indicating the mean shift. Rows indicate f2 given in Hz. Columns indicate the age contrast, with data shown for a modeled 4 month old infant (left column) and modeled 24, 48, and 96 month old infants (overlaid in the right column and distinguished by color). The shift reference limits are clearly f2-dependent; greater test retest variability is present at lower and higher f2’s. The shift reference limits are also age-dependent, with the greatest contrast found for the 4 month old infant relative to each of the other ages examined.