## 4 Discussion
### Serial Measurement of DPOAEs with and without Platinum Derivatives  
The need for specialized hardware and calibration techniques complicates the delivery and recording of acoustic stimuli at high frequencies (\(\geq\)8 kHz) in daily clinical practice where access to these capabilities are not commonplace or time- or cost-prohibited. Using customized equipment, high-frequency (\(>\)8 kHz) DPOAEs have been measured [21; 28] and are repeatable across testing sessions in normal-hearing young adults and children [28; 29; 43; 44], in those with cystic fibrosis tested betweenotoxic treatments [32], and identified the earliest signs of damage in adults exposed tootoxic agents [16]. Traditional calibration methods do not account for individual differences in ear canal geometry and acoustics impacting serial measurement comparisons, while more current in-the-ear calibration techniques attempt to overcome these individual differences through delivery of the signal at the desired level to each individual's eardrum (see reviews by [18; 19; 20]). Calibration errors due to standing waves are greatest above 2 kHz (particularly between 3-7 kHz in adults) [28] and applying a FPL calibration approach has demonstrated reduced variability compared to traditional calibration methods and better control of the delivery of stimulus levels at the eardrum [18; 19; 20]. Reduced variability across trials hold potential for more sensitive and reliable detection of the smallest changes due to ototoxicity (e.g., [2]).  
Figure 6 highlights a case illustration of the extension of DPOAE measures into the upper limit of human hearing for an individual undergoing cisplatin chemotherapy compared to an age-matched control subject to highlight serial measurement variability. As with any clinical tool, the utility depends in part on the variability of the measurement, which in the case of DPOAEs can differ based on a variety of factors (e.g., patient population, equipment used, probe placement, test location and method, stimulus parameters, middle ear status, tester, etc.). For monitoring purposes, several DPOAE measurements are made over time and compared to a baseline measure to determine a clinically significant change. To be considered clinically significant, DPOAE level differences from baseline must exceed test-retest variability making it critical to minimize the variability of controllable factors such as hardware, calibration technique, and test environment [2]. Any successful measure for ototoxicity monitoring needs to be consistent over time in the absence of pathology, so that the effects of the pathology can be confidently segregated from random fluctuation. DPOAEs at conventional frequencies have been found to be repeatable over short (days) and long (weeks) periods of time, with changes in level of 4-9 dB considered significant [45; 46; 47]. Repeated measures of DPOAE level are slightly more variable at frequencies above 8 kHz than below in normal-hearing individuals [29] as  
well as patients [16] due in at least part to accurate stimulus control at high frequencies described above. In Figure 6, reduced variability across trials 1-3 is noted in the control subject (right side) compared to the exposed patient. Test-retest differences across weeks were on the order of \(<\)3 dB for frequencies up to 20 kHz in the control subject permitting clinically significant changes for the exposed individual to be interpreted as \(>\)3 dB difference from baseline at two adjacent frequencies as opposed to \(>\)6 dB difference permitting earlier detection of change. To this end, 6 frequencies at trial 2 (compared to 3 with the 6 dB criterion) and 7 frequencies at trial 3 (compared to 5 with 6 dB criterion) were available for comparison to baseline results. Overall, repeatable measures of DPOAEs at high frequencies are feasible and hold clinical utility for improvingotoxic monitoring.