PONE-D-19-28132

Some t-tests for N-of-1 trials with serial correlation

PLOS ONE

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Even though the manuscript is well-written and statistically sound it is unclear what the overall impact of this approach would be in terms of real-world applications. If you could provide an additional real-world example that would satisfy review #1 concerns that would be appreciated.

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Reviewers' comments:

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

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 #1:

<h2>Major points</h2>

In my opinion, practical aspects of what you are proposing should be discussed more fully.

1) For example, as far as I can see, the methods you develop are for single case n-of-1 trials with many treatment periods per subject. Yet the practical example of fibromyalgia that you use to illustrate your approach fulfills neither of these conditions: many subjects are involved with and most if not all subject have short series for the type of approach your are developing. Of course, one advantage of developing methods for single subjects is that they can be used from the beginning. Methods for many subjects may have to wait a long time for subjects to accrue during which time early patients may be awaiting a decision.

2) Nevertheless, even if you specifically wish to avoid using information from other patients when making a decision for a given one, I think at the very least you ought to consider whether information about nuisance parameters (for example correlation coefficients) at least could be shared between patients.

3)If the design in pairs is used and treatment order is randomised, I would have thought that the naive standard errors for a t-test would be calculated approximately correctly. This is generally what is assumed in experiments subject to temporal or spatial (as in agriculture) correlation. Are you able to check this? Of course, the serial correlation may be more of a problem for a short single series than for the case of multiple sequences considered in the paper by Senn that you cited.

<h2>Minor points</h2>

Articles to go with nouns are missing in many places. Some examples are

1) L281 The variance

2)L361 The order

3) L496 The variance

Reviewer #2: Thank you for this contribution.

I propose a few minor changes that should improve the robustness of this manuscript:

Abstract: You do well to highlight the need for this type of work (indeed within patient correlation has been a concern), but the statement "existing methods require simulation..." contradicts your analysis, which itself involves MC simulations. I would clarify your intentions here either in the manuscript or consider revising this portion of the abstract.

Intro: Broaden your review of how many observations within patients are normal- I know some of my collaborators have seen upwards of 30. Review Blackston et al. and Nikles' work for how aggregated nof1s perform regardless of sample size and consider citing.

Methods: Good work overall. Please review Huber et al's work in 2007 on amitriptyline in an Nof1 setting and cite if necessary.

Thanks.

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Reviewer #1: Yes: Stephen Senn

Reviewer #2: No

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Some t-tests for N-of-1 trials with serial correlation

PONE-D-19-28132R1

Dear Dr. Landes,

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

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With kind regards,

Alan D Hutson

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: (No Response)

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: (No Response)

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Reviewer #2: No