HOUSE EAR INSTITUTE. Talk Outline I.Background: Evolution of the Stacked ABR II. Stacked ABR:...

HOUSE EAR INSTITUTE

“Stacked ABR: Fundamentals and Use in Small Tumor Screening”

Presentation prepared by Manuel Don, Ph.D.Electrophysiology Department

House Ear Institute, Los Angeles, CA.

Presented by Kathy Murphy, M.A. CCC-ABio-logic Systems Corp.

HOUSE EAR INSTITUTE

Talk Outline

I. Background: Evolution of the Stacked ABR

II. Stacked ABR: Rationale and Method

III. Stacked ABR: Studies

IV. Tumor Screening Protocol

V. Future Stacked ABR Work

Talk Outline

Manny Don:Tôi sẽ1) Giới thiệu tổng quan về điện thính giác thân não mở rộng( Stacked ABR)2) Bàn luận về phương pháp đo và phân tích ABR3)Điểm qua những nghiên cứu đã công bố và giới thiệu những số liệu của những đề tài nghiên cứu gần đây chưa được công bố với những khối u nhỏ 4) Đưa ra những biên bản ngắn gọn sàng lọc những khối u nhỏ 5) Những điểm nổi bật nhất của những nghiên cứu mở rộng của Stacked ABR trong tương lai.

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Background: Evolution of the Stacked ABR

A. Eighth Nerve Tumors

B. Standard ABR Tumor Detection

C. What Do Standard ABR Measures Represent?

D. Limitations of Standard ABRs

I. Background

Manny Don:Tôi sẽ điểm qua:1) Khối u dây VIII tự nhiên 2) ABR tiêu chuẩn đánh giá khối u.3) Giải thích những gì biểu hiện trên ABR tiêu chuẩn.4) Và thảo luận về các giới hạn của ABR tiêu chuẩn.

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I. Background

Manny Don:First, a brief discussion of eighth nerve tumors

Spoendlin and Schrott (1989)

(6 kHz)

(2 kHz)

(1 kHz)

Cross Section: Human Auditory Meatus

I. Background: Eight Nerve Tumors HOUSE EAR INSTITUTE

Manny Don:•This is a cross section through a human auditory meatus taken from some work published by Spoendlin and Schrott in 1989.It shows the spatial relationship of the auditory and vestibular nerve bundles. This relationship is important because acoustic tumors are, in reality, vestibular Schwannomas, i.e. tumors that arise from the Schwann cells of the vestibular nerves.I want to emphasize that cochleotopic representation in the auditory nerve as deduced from the representation of the turns shown in roman numerals, demonstrates that tumors arising from the vestibular nerves (superior and inferior) can affect auditory nerve fibers from both low and high frequencies. Note, for example that the fibers from turn II representing 1 kHz are, at this level, very close to the inferior vestibular nerve.

Cross-section of Internal Auditory Canal (IAC)

Facial Nerve

Acoustic Nerve

Sup.Vest. Nerve

Inf.Vest. Nerve


Manny Don:For the remainder of the talk, I will be using this schematic drawing of the cross-section through the internal auditory canal (IAC) which shows the four major nerve bundles: the acoustic nerve, the superior and inferior vestibular nerves, and the facial nerve.

Medium or Large Tumor in IAC

Facial Nerve

Acoustic Nerve

Sup.Vest. Nerve

Inf.Vest. Nerve

Tumor


Manny Don:This is a schematic illustration of how a medium or relatively large tumor arising from the superior vestibular nerve might encroach on the acoustic nerve fibers in the internal auditory canal.

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I. Background: Standard ABR

Manny Don:Next, I would like to review very briefly the standard ABR measures for tumor detection. In a publication a few years ago, Dr. Bauch and his colleagues showed that the best two standard ABR measures for tumor detection was the IT5 and the I-V delay.

Standard ABR Measures for Acoustic Tumor DetectionIT5 = Interaural time delay for wave V

14121086420 ms

7.3

6.4

L1

L2

Tumor Side

Non-Tumor Side

IT5 = L2 - L1 = 0.9 ms

I. Background: Standard ABR HOUSE EAR INSTITUTE

Manny Don:IT5 is a measure of the interaural time delay for wave V and was developed many years ago by Selters and Brackmann. One simply compares the latency of wave V between the tumor suspected ear and the non-involved ear. If the latency in the tumor suspected ear exceeds that of the non-involved ear by a certain criterion, the test is positive for a tumor. There is some correction factor for hearing loss.

Standard ABR Measures for Acoustic Tumor Detection:I-V Delay = Latency Difference Between Wave I and V

I-III Delay

I-V Delay

14121086420 ms

6.55

1.70

4.90

I IIIV

I - V = 4.85 ms

Acoustic Tumor

I. Background: Standard ABR HOUSE EAR INSTITUTE

Manny Don:The I-V delay is simply the latency difference between wave I and wave V of the ABR response in the suspected ear. If this delay exceeds a certain criterion value, this measure is positive for a tumor.

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“ABR yields high detection scores: up to 90%. The larger the tumor, the easier its detection. It is likely that small tumors (< 1 cm) will be missed.”

Eggermont JJ, Don M, Brackmann DE. Electrocochleography and auditory brainstem responses in patients with pontine angle tumors. Ann Otol, Rhinol, and Laryngol, Suppl. 1980; 75: 1-19.


Manny Don:Some 20 years ago, we concluded from a study of these two standard ABR measures in a large series of tumor cases, that these measures detected medium and large size tumors but that many tumors smaller than 1 cm would be missed. Studies over the last 10 years have confirmed this finding that standard ABR measures, frequently miss small tumors.

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Summary of Standard ABR Test Detects nearly all medium and large acoustic

tumors.

Misses 30-50% of small (<1 cm) acoustic tumors.

Consequence of failure to detect small tumors All patients with suspicious clinical hearing and balance symptoms are sent for Magnetic Resonance Imaging (MRI).


Manny Don:In summary of the use of standard ABR measures for detecting acoustic tumors, studies have shown that:(bullet 1)(bullet 2)The consequence of this failure and the advent of Magnetic Resonance Imaging or MRI is that for many clinics…In essence, MRIs are used to screen for acoustic tumors.

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Drawbacks of Screening with MRI

Relatively expensive ($2100)

Not available everywhere Invasive, anxiety producing, and uncomfortable test

for some patients Cannot be used on patients with implanted metal

devices or materials

Most patients tested do not have a tumor


Manny Don:However, there are some...

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Why do standard ABR measures often fail to detect small tumors ?

The obvious reason: Small tumors exert less pressure and affect a smaller number of

neural fibers than larger tumors. But, these not the only factors because: 1. Many of these small tumors exert enough

pressure to cause clinical symptoms. 2. Many small tumors are detected by standard

ABR measures.


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Why do standard ABR measures often fail to detect small tumors ?

Hypothesis: Standard ABR measures often fail to detect small tumors because these measures are dominated by activity from a subset of 8th nerve fibers that may not be affected by the small tumor.

Thus, the limitation is not with ABRs per se, but with the ABR measures used.


Manny Don:So, the question is,…Our hypothesis is:...

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I. Background/What Do Standard ABRs Represent?

Manny Don:In order to understand the failure of the standard ABR measures, we need to understand what these measures represent.

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The IT5 and I-V Delay Use Wave V Latency Measures:

What does the latency of the ABR wave V represent?


Manny Don:(self-explanatory)

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Two Prevalent Misconceptions About Click-evoked ABRs

1. Clicks have only high-frequency energy.

2. ABRs can only test cochlear function from 2 to 4 kHz.


Manny Don:To begin our discussion of what wave V latency in the ABR represents, I want to clear up ...

I. Background/What Do Standard ABRs Represent? HOUSE EAR INSTITUTE

Manny Don:First, let us take a look at the spectral energy of a click. Here we see the amplitude spectrum of a click that is produced by applying a 100 µsec pulse to a TDH-49 earphone. You can see that there is considerable energy from 5 kHz down to at least 200 Hz. Energy falls off above 5 kHz in part because of the response characteristics of the earphone and because of the width of the pulse. We will not discuss this further as there are several technical issues that go beyond the scope of this talk. The point here is that there is considerable low-frequency energy in a click stimulus.

1514131211109876543210 ms

60 dB nHL Clicks

Standard ABR

CF = 11.3 kHz

CF = 5.7 kHz

CF = 2.8 kHz

CF = 1.4 kHz

CF = 0.7 kHz

V

V

V

V

V

V


Manny Don:In this slide we have a series of ABR waveforms. The top trace (white) is the standard ABR obtained with wide -band click stimuli. The succeeding traces represent ABRs from octave wide regions of the cochlea. The center frequencies of these cochlear regions are noted to the left of each trace. I will discuss later how these ABRs from place-specific regions of the cochlea are obtained. Adding these traces together result in the standard ABR waveform shown in the top trace. The main point to see here is that, while the wave V latency of the standard ABR at the top is dominated by cochlear activity from the high frequency regions, there is considerable evoked activity from the lower frequency regions as well. However, this evoked activity from the lower frequency cochlear regions is phase cancelled and only the high-frequency contributions are evident.

1514131211109876543210 ms

60 dB nHL Clicks

Standard ABR

CF = 11.3 kHz

CF = 5.7 kHz

+11.3 kHz 5.7 kHz


Manny Don:This slide illustrates this point. The top trace is again the standard ABR to wide-band click stimuli. The next two traces are ABRs from octave-wide regions centered at 11.3 and 5.7 kHz. If these two ABRs are added together, the resultant waveform is shown in the bottom trace. Note that the latency as well as the amplitude of the standard ABR at the top is very close to that of the sum of just these two high-frequency ABRs.

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Take Home Messages A click stimulus is a wideband acoustic signal with

as much low-frequency energy as there is high-frequency (HF) energy.

The click-evoked ABR contains neural activity representing all frequency regions of the cochlea, not just the HFs.

In the standard ABR, wave V latency is dominated by HF regions because lower frequency contributions are phase-cancelled.


Manny Don:Self-explanatory

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I. Background/Standard ABRs Limitations

Manny Don:Let us now focus on the limitations of the standard ABRs with respect to small tumor detection.

Normal Internal Auditory Canal (IAC)

Facial Nerve

Acoustic Nerve

StandardABR

Sup.Vest. Nerve

Inf.Vest. Nerve

High-frequency

I. Background: Standard ABRs Limitations HOUSE EAR INSTITUTE

Manny Don:Let us now represent standard ABR in terms of the auditory nerve fibers in the internal auditory canal or IAC. I am not trying to show the actual distribution of the high-frequency fibers here in the auditory nerve bundle. The important point is that the high-frequency fibers which dominate the wave V latency of the standard ABR measure is only a subset of the fibers in the nerve bundle.

AbnormalStandardABR


Facial Nerve

Acoustic Nerve

Sup.Vest. Nerve

Inf.Vest. Nerve

Tumor


Manny Don:This illustrates how a large tumor will usually affect a large number of auditory nerve fibers especially those from the high-frequency regions. As a result, the standard ABR measure (latency) is abnormal.

Small Tumor in IACSup.

Vest. Nerve

AbnormalStandardABR

Facial Nerve

Acoustic NerveInf.

Vest. Nerve


Manny Don:A small tumor affects fewer fibers but could affect sufficient high-frequency fibers to cause an abnormal standard ABR latency measure. Abnormal standard ABR measures are obtained in about half of the small tumors cases.

Small Tumor in IAC

Facial Nerve

Acoustic Nerve

NormalStandardABR

Sup.Vest. Nerve

Inf.Vest. Nerve


Manny Don:However, it is easy to see the possibility that a small tumor could affect a small number of fibers that do not include very many high-frequency fibers. As a result, the wave V latency of the standard ABR could still be normal. Our hypothesis is that this is the reason the standard ABR fails to detect many small tumors.

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Summary The wave V latency used in standard ABR IT5 and

I-V delay measures is dominated by neural activity from high-frequency (HF) regions of the cochlea.

If the tumor does not affect these HF fibers sufficiently, the standard ABR latencies will be normal.

Small tumors do not always affect HF fibers, so they may be missed by standard ABR measures.


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Advantages of ABRs over MRIs

The ABR is:

Much less expensive

More widely available

Non-invasive

More comfortable than MRI

II. Stacked ABR: Rationale

Manny Don:What would be the advantages of developing an ABR measure for tumor screening instead of using the MRI test?

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The Challenge Can we develop an ABR test that:

1. Detects small tumors that cause symptoms, and

2. Significantly reduces the number of patients sent for MRI who do not have a tumor?


Small Tumor in IAC

Facial Nerve

Acoustic Nerve

NormalStandardABR

Sup.Vest. Nerve

Inf.Vest. Nerve

High-frequency

II. Stacked ABR: Rationale HOUSE EAR INSTITUTE

Manny Don:In order to develop an effective ABR test to screen for small tumors, we have to solve this problem where the tumor does not affect the nerve fibers that are critical for the ABR measure. In the case of the standard ABR, the high-frequency subset of fibers.

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Hypothesized that tumor detection fails with standard ABR measures because these measures are dominated by high-frequency activity and small tumors may not always affect the high-frequency fibers.

In order for a new ABR measure to detect small tumors, it must measure activity from essentially all fibers, not just a subset.


Normal IAC

Facial Nerve

NewABR

Acoustic Nerve

Sup.Vest. Nerve

Inf.Vest. Nerve


Manny Don:In other words, we need a new ABR measure that is based on essentially all the nerve fibers (encompassed by the black circle), not just a subset.

Normal IAC

Facial Nerve

NewABR

12

3

45

Acoustic Nerve

Sup.Vest. Nerve

Inf .Vest. Nerve

Stacked ABR: Rationale and MethodII. Stacked ABR: Rationale HOUSE EAR INSTITUTE

.

Manny Don:A solution would be to divide the whole auditory nerve into five groups and use the activity from these groups in a new ABR measure. These five groups could represent frequency regions of the cochlea that span the whole frequency range and, therefore, the the whole auditory nerve.

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Diagnostic Test: If you add the activity from each of the five areas, is the amplitude normal?

Activity from area 1+




Activity from area 5

12345

Normal Amplitude


Manny Don:An example of a...

3


New ABR: Abnormal

Normal Tumor

Acoustic Nerve

12345

Tumor


Manny Don:Let’s see how this new ABR test would work with the various tumor examples presented earlier: First, in example of the medium or large tumor, we can see that many fibers from areas 2,3, and 4 would be compromised. In addition to the fibers obscured by the tumor, stippled fibers represent fibers that are also affected by the encroaching tumor. Reduction of the contributions from these affected areas would result in an abnormally low overall amplitude of the added activity.

Small Tumor in IACNew ABR: Abnormal

Normal Tumor

Acoustic Nerve

12345


Manny Don:In the case where the small tumor affected sufficient high-frequency fibers to produce an abnormal standard ABR latency measure, it would also reduce the contribution from areas 2 and 3 and produce an abnormally low amplitude of the added activity from all areas.

Small Tumor in IAC

Facial Nerve

Acoustic Nerve

NormalStandardABR

Sup.Vest. Nerve

Inf.Vest. Nerve


Manny Don:Finally, let’s look at the case where the small tumor did not affect a sufficient number of high-frequency fibers, and therefore, the standard ABR latency measures were normal.

Small Tumor in IAC

New ABR: Abnormal

Normal Tumor

Acoustic Nerve

12345


Manny Don:For this troublesome case, the new ABR measure would still be abnormal because the contributions from areas 3 and 4 would be reduced, espcially area 4. Because this new measure involves contributions from essentially all the nerve fibers, it doesn’t matter where the tumor is located or which fibers are affected as long as there has been compromise of a sufficient number of fibers.

New ABR Measure Requirements

1. An auditory signal that stimulates essentially all frequency regions of the cochlea

2. A method for separating the responses from different frequency regions of the cochlea

3. A procedure for summing the responses to approximate total neural activity

Proposed Methods

Wideband Click

The Derived-band ABR Technique

The Stacking Technique


Manny Don:This new ABR measure that involves essentially all of the auditory nerve fibers is the Stacked ABR measure. The following is a list of the requirements of such a measure and the proposed methods for fulfilling the requirements. First we need ...

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Stacked ABR: Rationale and Method

A. Derived-band ABRs 1. Stimuli a. Clicks b. High-pass masking noise 2. Response subtraction

B. Stacking derived-band ABRsC. ABR recordings

II. Stacked ABR: Method

Manny Don:We begin our Stacked ABR discussion with the derived-band ABR method which fulfills the stimulus requirement and the procedure for separating out activity from different parts of the cochlea, and therefore, different subsets of auditory nerve fibers. The stimuli are clicks and high-pass masking noise. The responses to various combinations of clicks and high-pass noises are subtracted from each other to obtain the derived-band ABRs representing activity initiated from different frequency regions of the cochlea. I’ll demonstrate this later.

Click

High-pass Masking Noise

TDH-49

II. Stacked ABR: Derived-band ABRs/Stimuli HOUSE EAR INSTITUTE

Manny Don:Recall earlier that a click produced by a 100 µsec pulse results in a broad-band stimulus with energy in both high and low frequencies. This spectrum is shown again in the top trace. Thus, when presented at about 60 dB NHL, this click will stimulate most of the cochlea.The traces below show the spectrum of the high-pass masking noise that is used to mask activity from various parts of the cochlea.

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Click alone response (Standard ABR)

ApexFrequency kHz8 4 2 1 0.5

Base

Nerve Fibers

II. Stacked ABR: Derived-band ABRs/Response Subtraction HOUSE EAR INSTITUTE

ABR to Click Alone(Standard ABR)

Manny Don:Now I would like to demonstrate how we can use click stimuli and high-pass masking noise to obtain ABRs that are related to activity from a specific place and frequency region of the cochlea. In this slide, we see a schematic showing the nerve fibers coming from five regions of the cochlea. The five regions are color-coded and going from left to right, frequency goes from high to low. Shown below is a cross-section of the auditory nerve. When stimulated by a click, essentially all the fibers are activated and the resultant ABR (shown on the right) represents activity from all parts of the cochlea. This is the click-evoked standard ABR with which we all are familiar. I will refer to this as the standard unmasked ABR.

HOUSE EAR INSTITUTE


Base

Nerve Fibers

M

Click + 8 kHz High-pass masking noiseABR to Click + 8 kHz

High-pass Masking Noise


Manny Don:If we now present the clicks with 8 kHz high-pass masking noise, the resultant response comes from the unmasked regions of the cochlea, i.e., below 8 kHz. The masked portion, 8 kHz and above, is shown as blackened fibers.

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Derived-band ABR CF = 11.3 kHz


Base

Nerve Fibers

Click alone response (Standard ABR)


Base

Nerve Fibers


Base

Nerve Fibers

M

Click + 8 kHz High-pass masking noise

ABR to Click Alone (Standard ABR)

ABR to Click + 8 kHzHigh-pass masking noise


Manny Don:If we now subtract the 8 kHz masked response from the unmasked response, we obtain a derived-band response. Note that because the activity from below the 8 kHz region is in both the unmasked and 8 kHz masked conditions, this activity is removed by the subtraction process. Thus, the derived-band response represents activity only from above the 8 kHz region. Theoretically, this derived-band activity represents an octave wide region centered at about 11.3 kHz.

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Base

Nerve Fibers

ABR to Click + 4 kHz High-pass masking noise

M M


Manny Don:Next, if we present the clicks with 4 kHz high-pass masking noise, contributions from 4 kHz and above are removed. Thus, the resultant ABR represents activity from below the 4 kHz region.

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Base

Nerve Fibers


Base

Nerve Fibers

M

Click + 8 kHz High-pass masking noise


Base

Nerve Fibers


M M

M

ABR to Click + 8 kHzHigh-pass masking noise


Manny Don:If we now subtract the 4 kHz high-pass masked response from the 8 kHz high-pass masked response, we obtain the next derived-band response. By subtraction, the activity below 4 kHz which is common to both the 4 kHz and 8kHz masked response, is removed. The region above 8 kHz is masked in both conditions. Thus, the derived-band response represents activity between 4 and 8 kHz; activity that was unmasked in the 8 kHz condition but masked in the 4 kHz high-pass condition. Theoretically, this derived-band activity represents an octave wide region centered at about 5.7 kHz.

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Base

Nerve Fibers


M M M


Manny Don:Next, if we present the clicks with 2 kHz high-pass masking noise, contributions from 2 kHz and above are removed. Thus, the resultant ABR represents activity from below the 2 kHz region.

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Base

Nerve Fibers


M M


Base

Nerve Fibers


M M M



Base

Nerve Fibers

M M


Manny Don:As before, if we now subtract the 2 kHz high-pass masked response from the 4 kHz high-pass masked response, we obtain the next derived-band response. By subtraction, the activity below 2 kHz, which is common to both the 2 kHz and 4k Hz masked responses, is removed. The region above 4 kHz is masked in both conditions. Thus, the derived-band response represents activity between 2 and 4 kHz; activity that was unmasked in the 4 kHz condition but masked in the 2 kHz high-pass condition. Theoretically, this derived-band activity represents an octave wide region centered at about 2.8 kHz.

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Neural contributions fromdifferent frequency regionsof the cochlea can be obtained using the derived-band ABR method.

Derived-band ABRs represent activity from more specific frequency regions than moderate-to-high level toneburst-evoked ABRs.

14121086420 ms

V

Unmasked (Standard) ABR

VCF = 11.3 kHz

VCF = 2.8 kHz

V

CF = 1.4 kHz

VCF = 0.7 kHz

V

CF = 5.7 kHz

II. Stacked ABR: Method/Derived ABRs

Derived-band ABR Summary

Manny Don:Summary:...Note that the latency of wave V of the derived-band ABRs increase in latency as the frequency region it represents becomes lower. This progressive delay down the cochlea is the basis for the phase cancellation of the low frequency contributions to the unmasked response.

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A. Derived-band ABRs1. Stimuli a. Clicks b. High-pass masking noise2. Response subtraction

B. Stacking derived-band ABRs

C. ABR recordings

II. Stacked ABR: Method/Stacking

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CF = 0.7 kHzCF = 1.4 kHzCF = 2.8 kHz

CF = 11.3 kHz

CF = 5.7 kHz

Stacked ABR

14121086420 ms

Shifted to 5.7 kHzWave V latency

Sum ofShifted

Waveforms

The Stacked ABR is formed by first temporally aligning wave V of the derived-band ABRs, then summing the responses.

Aligning the derived-band ABRs eliminates phase cancellation of lower frequency activity. Thus, the Stacked ABR amplitude reflects activity from all frequency regions of the cochlea, not just the high frequencies.

Reduction of any neural activitydue to a tumor, even a smalltumor, will result in a reductionof the Stacked ABR amplitude.

The Stacked ABR Technique

II. Stacked ABR: Method/Stacking

Manny Don:The temporal shifting and aligning of the responses removes the phase-canceling effects. Thus, the resultant Stacked ABR represents contributions from all parts of the cochlea.

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14121086420 ms

Stacked ABR

CF = 11.3 kHz

CF = 5.7 kHz

CF = 2.8 kHz

CF = 1.4 kHz

CF = 0.7 kHz

14121086420 ms

Derived-Bands Aligned(Shifted and summed)

Derived-Bands (Actual timing)

Standard ABR

Stacked ABR

II. Stacked ABR: Rationale and Method--Stacking derived-band ABRs

Manny Don:The next series of slides will illustrate how amplitude measures of the standard ABR fail to reflect all the neural activity whereas the Stacked ABR does. This slide shows for a non-tumor normal hearing individual the standard ABR and the derived bands with their natural delays in the left panel. The right panel shows the same waveforms but aligned to form ths Stacked ABR.

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14121086420 ms

CF = 11.3 kHz

CF = 5.7 kHz

CF = 2.8 kHz

CF = 1.4 kHz

CF = 0.7 kHz

14121086420 ms

10% Reduction }

Standard ABR Standard ABR minus 2 bandsExample 1


Manny Don:This illustrates what happens to the amplitude of the standard ABR if activity from the lowest two frequency bands are removed. The amplitude drops by only 10%.

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ms

Example 1

33 % Reduction

Stacked ABRs Stacked ABR minus 2 bands

14121086420 ms

14121086420

CF = 11.3 kHz

CF = 5.7 kHz

CF = 2.8 kHz

CF = 1.4 kHz

CF = 0.7 kHz


Manny Don:For the same individual in the previous slide, this illustrates how the removing the lowest two frequency bands reduced the Stacked ABR by 33%. This shows how the Stacked ABR is more sensitive to the reduction of neural activity evoked by the click.

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14121086420 ms

14121086420 ms

CF = 11.3 kHz

CF = 5.7 kHz

CF = 2.8 kHz

CF = 1.4 kHz

CF = 0.7 kHz

Standard ABR minus 2 bandsStandard ABR

12% Increase }

Example 2


Manny Don:This is a more dramatic illustration from another non-tumor normal-hearing individual as to what happens to the amplitude of the standard ABR if activity from the lowest two frequency bands are removed. The amplitude actually increases by 12%. The reason for an increase instead of an expected decrease is due to a variation in the phase canceling effects of the two lower frequency bands.

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Stacked ABR

23 % Reduction

Stacked ABR minus 2 bands

14121086420 ms

14121086420 ms

CF = 11.3 kHz

CF = 5.7 kHz

CF = 2.8 kHz

CF = 1.4 kHz

CF = 0.7 kHz

Example 2


Manny Don:For the same individual in the previous slide, this illustrates how the removing the lowest two frequency bands reduced the Stacked ABR by 23% whereas the standard amplitude had increased by 12%. It is logical to expect a reduction instead of an increase when activity is removed. This again shows how the Stacked ABR is more sensitive and reflects reduction of neural activity evoked by the click.

Normal IAC

Facial Nerve

NewABR

12

3

45

Acoustic Nerve

Sup.Vest. Nerve

Inf .Vest. Nerve


II. Stacked ABR: Stacking HOUSE EAR INSTITUTE

STACKED

.

Manny Don:Thus, in summary, the Stacked ABR represents activity from all parts of the cochlea and should be more sensitive to small tumors.

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A. Derived-band ABRs1. Stimuli a. Clicks b. High-pass masking noise2. Response subtraction

B. Stacking derived-band ABRs

C. ABR recordings

II. Stacked ABR: Method/ABR Recordings

Manny Don:I would like to take a few moments to discuss some aspects about ABR recordings that are critical to the Stacked ABR.

ABR Recordings

Amplification: 5 X 105

Filter Passband: 0.1 - 3 kHz Filter Slope: 12 dB/octave

II. Stacked ABR: Method/ABR Recordings HOUSE EAR INSTITUTE

Cz - Positive 50% (nasion to inion) 50% (ear to ear)Ipsi Mastoid - NegativeContra Mastoid - Ground

Electrode Recording Montage

Manny Don:The recording parameters in terms of amplification, filter passband, and filter slope are fairly standard. To facilitate consistency in our recordings and to reduce variability in our database, our Cz electrode is located at the intersection that is midway between the nasion and inion and midway between the two ears. We record differentially between Cz and the ipsilateral mastoid.

ABR Recordings

1. Estimation of Unaveraged Noise (Fsp estimation)

2. Weighted Averaging (Bayesian weighting)

3. Termination of Averaging When Residual Noise Level is low ( 20 nV)

Minimization of Physiological Noise in ABRs

II. Stacked ABR: Method/ABR Recordings HOUSE EAR INSTITUTE

Manny Don:An important aspect of the Stacked ABR is to make sure that the derived-ABR responses that are “stacked” have minimal physiological noise. We want the measure to represent neural activity related to stimulation rather than background physiological noise. To accomplish this, we perform estimates of the residual noise in the ABR, perform an average that is weighted towards blocks of sweeps that have the least physiological background noise, and terminate the averaging when the estimate is a low 20 nV.

II. Stacked ABR: ABR

Recordings/Noise HOUSE EAR INSTITUTE

Manny Don:This slide is taken from some work by Claus Elberling demonstrating the effect of the averaged noise on the recorded ABR. It should be remembered that the recorded ABR contains both the “true ABR” and the averaged background noise. In reality, we cannot separate out these two contributions to the recorded ABR. The hope is that we perform sufficient averaging to reduce the averaged background noise to a level where it is contributing little to the recorded ABR so that the recorded ABR is a good representation of the ‘true ABR”. In this slide, we see how on one run the averaged noise has a waveform that has random peaks that coincide with the true ABR wave V peak. Thus, the recorded ABR has a an amplitude that is larger than the true amplitude. On another run, a random noise peak is antiphasic with the true ABR wave V peak and the recorded ABR wave V is much smaller. This is the major reason that wave V amplitude seems to vary from run to run. Thus, it is important to average until the residual noise in the waveform is very small so that the recorded ABR is a close reflection of the true response.

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ABR Recordings





II. Stacked ABR: Rationale and Method--ABR recordings

HOUSE EAR INSTITUTEII. Stacked ABR: Rationale and Method--ABR recordings

Manny Don:This illustrates the difference in waveform repeatability when a fixed number of sweeps are used (left panel) vs when a fixed signal to noise ratio (Fsp value- from paper by Elberling & Don, 1984). Demonstrates that the run to run variability is mainly due to the averaged noise.

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ABR Recordings







Subject 1 Theoretical Subject 1 EstimatedSubject 2 Estimated

Estimated Residual Noise as aFunction of Accepted Sweeps

Accepted Sweeps0 2000 4000 6000 8000 10000

nV R

MS

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Manny Don:Plots of the estimated residual noise in an ABR as a function of the number of sweeps averaged. Illustrates that the key to low residual noise is a quiet person. Subject 1 is noisy but the reduction of the noise with averaging is predicted by the averaging principle (√N). At end of nearly 10,000 sweeps noise in the average is barely equivalent to subject 2 after 500 sweeps. Averaging can only do so much.

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Normal Averaging Weighted Averaging

(0.8)

(0.5)

(19.8)

(1.0)

(0.3)

(31.7)

(2.03)

(17.2)(17.4)

Avg. (X4)

(1.35)

(1.18)

(0.04)

(3.20)

(0.05)

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Avg. (X4)


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Manny Don:Figure from Elberling and Wahlgreen (Scand. Audiol., 1985) comparing results of normal averaging (all sweeps equally weighted, left panel) versus weighted averaging using the Bayesian estimation technique to weight blocks of sweeps according to the amount of estimated residual noise in that block of sweeps (right panel). Get better reproducibility with weighted average. This minimizes the destructive effect of episodic noise shown in previous slide.

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0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Accepted Sweeps

nV R

MS

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5

ActualTheoreticalBayes

Effect of Bayesian Weighting on Estimated Residual Noise


Manny Don:Illustrates how the Bayesian estimation for weighted averaging essentially removes the deleterious effect of the episodic noise shown two slides previously.

Gold filled triangles show how the estimated residual noise nearly mimics the theoretical noise levels when using the Bayesian estimation technique for weighted averaging.

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Summary of Noise in ABRs

All ABRs contain unaveraged backgroundphysiological noise (i.e. residual noise)

Methods for estimating the amount ofnoise in the ABR can be used to: 1. Give greater weight to sweeps with the lowest noise, and

2. Determine when to stop averaging.

II. Stacked ABR: ABR Recordings/Noise

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CAUTION!

Since the Stacked ABR is an amplitude measure, the amount of noise left in the response is critical.

For a more accurate estimate of neural activity, the residual noise level must be low.

If the residual noise level is high, then the Stacked ABR must be interpreted with caution.


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ABR Recordings

1. Estimation of Unaveraged Noise (Fsp estimation) 1. Estimation of Unaveraged Noise (Fsp estimation)

2. Weighted Averaging (Bayesian weighting)2. Weighted Averaging (Bayesian weighting)

3. Termination of Averaging When Residual 3. Termination of Averaging When Residual Noise Level is low ( 20 nV) Noise Level is low ( 20 nV)




Residual Noise Criterion

Estimated Residual Noise as aFunction of Accepted Sweeps

Subject 1 Theoretical Subject 1 EstimatedSubject 2 Estimated

0 2000 4000 6000 8000 10000Accepted Sweeps

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nV R

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Manny Don:To insure that the stacked ABR is composed of averages that contain mostly evoked neural responses, averaging is terminated when the residual noise is 20 nV or less. Based on this conservative criterion, subject 1 would not have achieved criterion in over 10000 sweeps whereas subject 2 achieved this level in about 1500 sweeps. Now exploring if the criterion noise level can be raised without compromising the effectiveness of the Stacked ABR.

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Clinical Judgement There will be cases where the residual noise

level remains high even after thousands of sweeps.

In these cases, make sure the patient iscomfortable and as relaxed as possible before you continue.

If the patient remains noisy, then the Stacked ABR must be interpreted with caution.


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Take Home Message 5

Residual noise levels must be low so that the Stacked ABR amplitude mostly reflects total neural activity, not noise.

Stacked ABRs formed from noisy recordings may be unreliable and should be interpreted with extreme caution.

Questions?


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Talk Outline






Talk Outline

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Stacked ABR: Studies

A. Interpretation of Results 1. Basics of Data Presentation 2. Sensitivity vs. Specificity

B. Published Study

C. Preliminary Work

III. Stacked ABR/Interpretation of Results

X

Normal Distribution

Cumulative Distribution

X

10%

25%

50%

75%

90%

10%

25%

50%

75%

90%

Perc

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III. Stacked ABR: Results/Data Presentation HOUSE EAR INSTITUTE

Manny Don:In the top graph is the well know normal distribution curve. It simply describes how the values of X are distributed in a population. The mean X value of this normal distribution is here where the peak of the distribution occurs. In essence, 50% of the population have values less than this mean and 50% of the population have values greater. The x value where 75% occurs, means that 75% of the population have values at or below and 25% have values above. This normal distribution can be replotted in terms of a cumulative distribution shown at the bottom. These percent values now form the y-axis with the X values on the x-axis. From this cumulative curve, we can pick any x value and determine what percent of the population have values equal or lower, or vice versa.

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50% of the test population have Stacked ABR amplitudes that fall below what value?

Cumulative Distribution Curve

Stacked ABR (nV)200 400 600 800 1000 1200 1400

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880 nV

50

III. Stacked ABR: Results/Data Presentation

Manny Don:Let’s use the example of the distribution of Stacked ABR values plotted on a cumulative curve. If we ask, 50% of the test population have Stacked ABR amplitudes that fall below what value? We simply find where the 50% point intersects the curve and from that point where it intersects on the amplitude axis. The answer in this case is 880 nV.

What percentage ofthe test population has Stacked ABR amplitudes < 1000 nV?

Cumulative Distribution Curve

Stacked ABR (nV)200 400 600 800 1000 1200 1400

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82 %

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III. Stacked ABR: Results/Data Presentation

Manny Don:Going the other direction, we can ask, “What percentage of the test population has Stacked ABR amplitudes less than 1000 nV. From the 1000 nV point we draw a line to the cumulative distribution curve and from that intersection with the curve we draw a line to where it intersects the percentage axis. In this case, it is determined that 82% of the test population have Stacked ABR amplitudes equal to or less than 1000 nV.

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Sensitivity vs. Specificity of an ABR Measure

Sensitivity

For a given criterion of an ABR measure, the sensitivity is defined as the percentage of tumor cases detected (i.e., the true-positive rate).

Specificity

For a given criterion of an ABR measure, the specificity is defined as the percentage of non-tumor cases that are correctly identified (i.e., the true-negative rate).

III. Stacked ABR: Results/Sensitivity vs. Specificity

Criterion 100% Sensitivity

(i.e. all tumors detected)

25% Specificity(i.e. 75% non-tumors

misdiagnosed)

ABR Test Measure

Tumor Non-Tumor

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75

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0

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cent

ile

100% Tumors Detected

75% False-Positives

Criterion

III. Stacked ABR: Results/Sensitivity vs. Specificity HOUSE EAR INSTITUTE

Manny Don:At the top of this figure are the distributions of an ABR test measure for the non-tumor and tumor populations. We can see that the values for the non-tumor population are greater than for the tumor population. These distributions are replotted below as cumulative distributions. If we wanted to use this test measure to detect all of the tumors in this population, we would choose the ABR test value indicated by the vertical dash line. You can see that all values for the tumor population lie below the value indicated by this vertical line. Thus, for this criterion, the sensitivity is 100% in that all tumors would be detected because all tumors had values that were less than the criterion value. However, selecting this criterion would correctly identify only 25% of the non-tumor population. The specificity would be only 25%. That is 75% of the non-tumor population also have values that fall below the selected criterion and would have a positive (false positive) result.

Tumor Non-Tumor

100

75

50

25

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cent

ile

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ABR Test MeasureCriterion

10% False-Positives

75% Tumors Detected Criterion 90% Specificity

(i.e. 90% non-tumors correctly identified)

75% Sensitivity(i.e. 25% tumors missed)


Manny Don:If you wanted to select another criterion that would provide better specificity,for example 90%, the criterion value required is shown here by the dashed vertical line. With this criterion, 90% of the non-tumor cases would be correctly identified. However, we can see that for this criterion value, only 75% of the tumor case would be detected. That is, the sensitivity is now only 75%. It is important to remember that for any given ABR test measure, the distributions are defined. Selecting any criterion value determines the sensitivity and specificity. By selecting a different criterion value, one does not change the separation of the distributions. Therefore, if one changes the criterion to improve sensitivity, the specificity will be compromised; if one changes the criterion to improve specificity, then the sensitivity will be worse.

Take Home Message For any ABR test, the relationship between sensitivity and

specificity is determined by how well the measure separates the tumor and non-tumor populations.

Therefore, for any ABR test:

(1) Changing the diagnostic criterion to increase sensitivity will decrease specificity. In other words, changing the criterion to detect more small tumors will increase the number of misdiagnosed non-tumor patients (i.e. increase the false-positive results).

(2) Changing the diagnostic criterion to increase specificity will decrease sensitivity. In other words, changing the criterion to increase the number of correctly identified non-tumor patients (i.e. to decrease the number of false-positives) will increase the number of small tumors that are missed.


Criterion 100% Sensitivity


80% Specificity(i.e. 80% non-tumors correctly identified)

100

75

50

25

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Per

cent

ile


Tumor Non-Tumor

20% False-Positives20

NEW ABR Test MeasureCriterion


The only way to increase both sensitivity and specificity at the same time is to use an ABR measure that separates the non-tumor and tumor populations better.

Manny Don:“The…better”. Here we show a new ABR test measure that separates tumor population from the non-tumor population better than the example shown earlier. Now, the criterion that yields 100% sensitivity, i.e. detection of all tumors, also has a specificity of 80%, i.e. correctly identifies 80% of the non-tumor population.

Standard ABR vs. Stacked ABR

Stacked ABR Measure(Wave V Amplitude)

Standard ABR Measure(e.g., IT5 or I-V Delay)

Non-TumorSmall Tumor

Criterion

Small Tumor

Criterion

Non-Tumor


Manny Don:We can view the poor performance of the standard ABR measures as a problem of highly overlapped distributions of these measures for small tumor patients and non-tumor patients. We now want to demonstrate how the distributions of the Stacked ABR measures for these populations are more separated allowing high sensitivity and relatively high specificity.

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SUBJECTSAcoustic Tumor Subjects (N = 47)

Small (< 1 cm) tumors, irrespective of standard ABR results Tumors not detected by standard ABR measures, irrespective of the tumor size

Males Females Total Right Ear 14 7 21

Left Ear 15 11 26

Individuals 29 18 47

Age Range 32-68 years 25-66 years

Mean Age 48 years 49 years

III. Stacked ABR: Studies/Preliminary Work

Manny Don:I will review our results with 47 tumor cases. The population criteria were tumors not detected by the standard ABR measures (IT5 and I-V delay) irrespective of tumor size or that the tumor was equal to or less than 1 cm irrespective of standard ABR results. This table shows the distribution of the tumor patients with respect to gender, ear, and age of patient.

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SUBJECTSNon-tumor Normal-hearing Subjects (N = 73)

House Ear Clinic patients with negative MRI results House Ear Institute and Clinic employees, families, and friends

Males Females Total Right Ear 13 27 40

Left Ear 17 16 33

Individuals 30 43 73

Age Range 18-37 years 18-51 years

Mean Age 26 years 30 years


Manny Don:The control reference group was composed of 73 non-tumor normal-hearing subjects. These included patients with negative MRI results and other normal-hearing subjects recruited from employees of the House Ear Institute and House Ear Clinic and their family members and friends. This table shows the distribution for the non-tumor population with respect to gender, ear, and age of patient.

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Pure Tone Averages for 47 Small Tumor Cases

0102030405060708090

100

Perc

ent

-10 0 10 20 30 40 50 60PTA


Manny Don:In this slide we show the cumulative distribution curve for the 47 small tumor cases with respect to the Pure Tone Average (PTA) of the standard audiometric frequencies from 500 Hz to 8 kHz. Note that nearly 45% of this tumor population had PTA values 20 dB or less and about 33% had PTAs 15 dB or lower. In essence, many of the small tumor cases have fairly good audiometric thresholds.

HOUSE EAR INSTITUTE

.4

.8

-.6-.4-.2

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.6

11.21.41.61.8

22.22.42.6

IT5

-10 0 10 20 30 40 50 60PTA

Abnormal

Normal

N = 35 Detected (19) Missed (16)


Manny Don:Of these 47 tumor cases, we were able to obtain the IT5 values in 35 cases. Only 54% (19/35) of the tumors were detected by the IT5 test. It can be seen that several of the tumor cases missed actually had shorter wave V latencies (negative IT5s) in the tumor ear. To change the criterion to detect most of the tumors would result in a negative IT5 value and, therefore, would include most of the non-tumor cases, (i.e. very poor specificity). In this slide, we also show the relationship between the PTA and the IT5 value. Using the standard 0.2 ms IT5 as the criterion for a positive tumor test, note that when a tumor was missed by the IT5 (filled red circles), the PTA was generally less than 32 dB. Moreover, all the cases where the PTA was greater than about 32 dB, the IT5 detected the tumor. So, it appears that patients with small tumors that are missed by the standard ABR, have no more than a mild hearing loss. This observation will be of importance to our future work with then Stacked ABR.

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I-V Delay

I-V d

elay

in m

sObservations

3.03.23.43.63.84.04.24.44.64.85.05.25.45.65.8

6Tumors - Females N = 9(b)

Observations3.03.23.43.63.84.04.24.44.64.85.05.25.45.65.8

6

(a)

I-V d

elay

in m

s

Tumors - Males N = 16

Tumors - FemalesN = 9

Tumors - MalesN = 16

Detected (4) Missed (12)

Detected (2) Missed (7)


Manny Don:With regard to the other standard ABR measure, the I-V delay, reliable recordings were obtained in 25 of the small tumor cases (16 males and 9 females). Using 2 standard deviations from the mean of non-tumor normal hearing individuals, only about 25% of the tumor cases were detected. Again, to change the criterion to detect most of the tumors would result in a very short I-V delay value and, therefore, would include most of the non-tumor cases, (i.e. very poor or no specificity).

III. Stacked ABR: Studies/Preliminary Work HOUSE EAR INSTITUTE

Sen

sitiv

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ntile100% Sensitivity



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Tumor Non-Tumor

20% False-Positives20

NEW ABR Test MeasureCriterion

100% Sensitivity(i.e. all tumors

detected)


Manny Don:Recall that to achieve high sensitivity and good specificity, we need a new ABR measure that better separates the small tumor and non-tumor populations. We believe that the Stacked ABR measure separates these populations much better to allow a criterion value that results in high sensitivity and good specificity for small tumors.

Males Tumors Normal-Hearing Non-Tumor

93% Specificity

Target = 50% Specificity

100% Sens

Target = 95% Sensitivity

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Stacked ABR nV


Manny Don:In this figure are plotted the cumulative distributions of the Stacked ABR values for the subjects. The open light blue circles are for the non-tumor normal-hearing subjects (N=30) and the filled orange circles represent the small tumor cases (N=29). If we choose a criterion Stacked ABR value that yields 95% detection (left y-axis) or sensitivity, this value results in a specificity of 93% (right y-axis). If we change the criterion to detect all of the tumors in this population, the specificity would still be over 50%. This would suggest that we could screen and catch all the tumors and still reduce a significant number of non-tumor patients sent for imaging using this Stacked ABR measure.

Females Tumors Normal-Hearing Non-Tumor

Stacked ABR nV

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78% Specificity

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Target = 50% Specificity

0 200 400 600 800 1000 1200 1400 1600


Manny Don:In this figure, we plot the cumulative distribution curves of the Stacked ABR for the female subjects (small tumor N=18 and non-tumor = 43). The Stacked ABR value that results in 95% sensitivity (left y-axis) or detection, yields a specificity of 78% (right y-axis). Again, the criterion value for 100% detection yields a specificity of over 50%.

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Take Home Message The Stacked ABR appears to have better

sensitivity and specificity than the Standard ABR for small (<1 cm) tumors.

In other words, the Stacked ABR is better at :1. detecting small tumors, and2. decreasing the number of misdiagnosed non-tumor patients (i.e. decreasing the number of false-positives referred for MRI).


Manny Don:Self-explanatory

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Talk Outline






Talk Outline

Manny Don:I want to briefly outline a simple screening protocol for acoustic tumors.

Perform Standard ABR Analyses (IT5, I-V, etc.)

Send For An MRI

No

Perform Stacked ABR Analyses

No

Observe? Follow?

ABR SCREENING PROTOCOL FOR

ACOUSTIC TUMORS

Yes

Tumor?

Yes

Yes

Prescribe Treatment

(e.g., surgery)

Evaluate for auditory

neuropathy and/or

refer for neurological evaluation

No

Send For An MRI

Normal?

Normal? Tumor?Yes

No

IV. Stacked ABR: Screening Protocol HOUSE EAR INSTITUTE

Manny Don:Recall that the simple standard ABR measure detect nearly all medium and large size acoustic tumors and close to half the small tumors. Thus, for an efficient screen, the following protocol could be performed. 1) Measure the standard IT5 and or I-V delay. If either of these values are abnormal, the patient is referred for imaging. There is no need to perform the Stacked ABR.2) If these standard values are abnormal, and suspicion is still aroused, the Stacked ABR should be performed. If it is abnormally low, then the patient is referred for imaging.3) If the Stacked ABR is normal, then the patient should be observed and followed.

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Talk Outline






Talk Outline

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Future Stacked ABR Work

Optimization and Refinement of the Stacked ABR 1. Interaural comparisons

2. Hearing loss compensation3. Faster stimulus rates

Development of an automated clinical prototype

V. Future Work

Manny Don:In our NIH funded work we are investigating the following optimizations and refinements to the Stacked ABR method:1)We believe that interaural comparisons, when obtainable, will improve the sensitivity of the Stacked ABR.2) We believe that specificity might be improved by taking into consideration the effect of hearing loss.3) We also believe that using faster click rates will increase the separation between the small tumor from non-tumor populations.

HOUSE EAR INSTITUTE

Development of an Automated Clinical Prototype

Bio-logic Systems Corp.: Licensed by the House Ear Institute to collaborate on development of an automated version of the Stacked ABR.

Multi-Center Study: For validation of the Stacked ABR method and evaluation of the automated prototype.

(NIH SBIR Phase II Awarded to Bio-logic Systems Corp.)

V. Current Developments and Future Stacked ABR Work

Staff Acknowledgements

Department of ElectrophysiologyBetty Kwong, M.S., CCC-A

Chiemi Tanaka, M.A., CCC-AMichael Waring, Ph.D.

Department of Clinical StudiesAnn Masuda, M.S., CCC-A

Department of HistopathologyFred Linthicum, M.D.

Physicians at the House Ear Clinic

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SupportNIH/NIDCD 1R43 DC04141 Raviv (PI)NIH/NIDCD 2R44 DC04141 Raviv (PI)NIH/NIDCD R01 DC03592 Don (PI)

HOUSE EAR INSTITUTE. Talk Outline I.Background: Evolution of the Stacked ABR II. Stacked ABR:...

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