PONE-D-20-22709

Systematic review and meta-analysis of late auditory evoked potentials as a candidate biomarker in the assessment of tinnitus

PLOS ONE

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Reviewers' comments:

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: This study aim to elucidate the potential role of the auditory evoked response as biomarker in the study of patients with tinnitus. Using a multivariate meta-analytic study, the authors analyze the differences in the Late auditory evoked potentials (LAEPs) between tinnitus patients and controls described in twenty-one articles. The main result was a significantly poorer response of the p300 component in tinnitus patients, manifested by a reduction in amplitude and an increase in latency.

The manuscript is novel, since there is no previously published meta-analysis for the same purpose. The writing is adequate and its reading is fluid to the reader. The authors had a correct control of the Bias and risks, which allows us to think about the development of studies aimed at establishing the p300 component as a biomarker in the study of tinnitus.

In my opinion, there are some minor issues that should be considered for the publication of the manuscript:

Abstract:

L29: I recommend to use the concept potential biomarker

Discussion:

Since it does not appear in fig. 3, I recommend discussing how many of the articles analyzed showed significant differences in latency and / or amplitude of the p300, between the groups

A variable not included in the study is the use of central nervous system depressant medications by tinnitus patients. I recommend discussing it as a potential bias of the study, since it is known that this class of drugs and others affect the auditory evoked response.

Figure:

I recommend improving the resolution of figures 1, 2 and 3 in the final manuscript

Reference

Half of the articles summarized in Table 1 are not in the reference list (shiraishi 1991; Attias 1993, 1996; Jacobson 1996, 2003; Walpurger 2003; Dornhoffer 2006; Yang 2013; Houdayer 2015; Hong 2016, Gopal 2017)

Reviewer #2: This is a systematic review of late auditory potential measurements in tinnitus patients. It is an important piece of work, and I am glad the authors took the effort to produce this review. The outcome is that in tinnitus patients, the P300 component of the auditory response is reduced in amplitudes and delayed in comparison to that in subjects without tinnitus. The authors dealt with the very heterogenous literature in a very thoughtful way.

A consequence is that studies have been dealt with in a heterogeneous way. Therefore

I invite the authors to present the final model of Fig. 3 in some sort of graphical way, clarifying the dependent (various P and N-peaks) and independent (tinnitus, hearing threshold, age) variables

Some additional comments:

L51: This paragraph is a bit odd, as it appears to describe how tinnitus patients are clinically assessed. The first sentence claims that this work is done by an ENT physician or an audiologist. However, in many tinnitus centers the patient is evaluated by both and additionally a psychologist. Here, you only need to briefly summarize the subjective measures (questionnaires etc). I think this paragraph is only intended to contrast the next paragraph, where objective measurements are introduced.

Fig. 2: Is this real data? I think it is just a cartoon to illustrate your computation. Please clarify in the text.

L187: There is a funnel plot for P100 included in the supplemental material. As P300 is the most important outcome, I suggest to include funnel plots of P300 amplitude and delay. I suggest to put this in the main text, rather than in an appendix.

Fig. 3:

- It is confusing that the diamonds in the forest plot also appear as light grey diamonds overlapping with the results of individual studies. I suggest to remove those grey diamonds.

- Please double check the credibility intervals of P300 latency and amplitude. It seems odd that they are much larger than the 95% confidence intervals of the individual studies.

L207: The phrase 'Both of these authors' refers to two multi-author papers. Please correct.

L369: It is unclear to me whether age and hearing threshold were included as co-variates in the multivariate meta-analysis. This is important to do, and age and hearing loss is available for many studies. Please clarify. Please consider to perform a seperate analysis on the subclass of studies where age and hearing loss are both available.

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Reviewer #1: No

Reviewer #2: No

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Systematic review and meta-analysis of late auditory evoked potentials as a candidate biomarker in the assessment of tinnitus

PONE-D-20-22709R1

Dear Dr. Cardon,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Paul Hinckley Delano, Ph.D.

Academic Editor

PLOS ONE

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