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May
03

What it took to get the paper out

Our new paper took a while to make it out into the world..here is a view of reviews and editorial decisions..This is just the tip of the iceberg..the initial reviews and in most cases rejections are shown below.

So first we tried Science as a Brevia…The review came back in 7 May 2012 – - rejected

(Note some addresses and phone numbers, emails etc removed to avoid spammers)

Manuscript number: 1224145
Dear Dr. Ekins:
Thank you for submitting your manuscript “Dispensing Processes Impact Computational and Statistical Analyses” to Science. Because your manuscript was not given a high priority rating during the initial screening process, we will not be able to send it out for in-depth review. Although your analysis is interesting, we feel that the scope and focus of your paper make it more appropriate for a more specialized journal. We are therefore notifying you so that you can seek publication elsewhere.
We now receive many more interesting papers than we can publish. We therefore send for in-depth review only those papers most likely to be ultimately published in Science. Papers are selected on the basis of discipline, novelty, and general significance, in addition to the usual criteria for publication in specialized journals. Therefore, our decision is not necessarily a reflection of the quality of your research but rather of our stringent space limitations.
Sincerely,
Jake S. Yeston, Ph.D. Senior Editor
Then we tried Science again.. 14 June 2012 again rejection
Manuscript number: 1225655
Dear Dr. Ekins:
Thank you for resubmitting your manuscript “Dispensing Processes Impact Assays and Analyses” to Science. I regret that we still feel the scope and focus of the manuscript would be more appropriate for publication in a medicinal chemistry journal, where practitioners in the field are still likely to see it and appreciate the implications. We are now receiving more than ten times the number of submissions that we have space to publish, and so are obligated to turn away a great deal of outstanding work. We wish you every success in publishing the study elsewhere.
Sincerely,
Jake S. Yeston, Ph.D. Senior Editor

Then we tried Analytical chemistry Oct 11 – 2012 – Apparently the editor sent out 6 invites for review and only one responded..They rejected it

Journal:  Analytical Chemistry Manuscript ID: ac-2012-02719s Title: “Dispensing Processes Profoundly Impact Biological Assays and Computational and Statistical Analyses” Author(s): Ekins, Sean; Olechno, Joe; Williams, Antony
Dear Dr. Ekins:
I am reporting on the above manuscript, which you recently submitted for consideration in Analytical Chemistry.
After a careful study of the manuscript and considering the reviewers’ comments, I regret to inform you that I have decided against publication.  The potential usefulness of your work is not in question.  However, in light of the reviewers’ evaluation and comments, I do not believe that publication is justified.  I hope you will find the reviewers’ specific comments helpful in planning future work.  These comments are either included here or, if they were given in the form of a file, will appear at the bottom of the copy of this letter which will appear and be stored in your Author Center.
I appreciate the opportunity to have considered this contribution, and thank you for your interest in Analytical Chemistry.
Kind regards,
John Yates Associate Editor Analytical Chemistry

————————————
Reviewer(s)’ Comments to Author: Reviewer: 1
Recommendation: Should not be published in Analytical Chemistry.
Comments: This paper compares two liquid handling approaches, namely, the acoustic vs. tip-based dispensing.  Table 1 is the key table for this comparison, indicating values for LogP and LogD parameters.  While there are differences between N=14 and N=16, the first and last data columns, N=14 (acoustic) and N=24 (tip-based) show no statistically significant differences and closely match each other.  This indicates that increasing the sample size analyzed (i.e., number of samples) with the tip-based approach can off-set the error.  Based on my experience in 3 pharmaceutical companies, these types of correlations (using a tip-based approach) is often done with a large sampling size (N=50, N=100,…) anyway.  Thus, the paper does not present a convincing case and should not be published in Analytical Chemistry.  Lastly, bunch of measured acoustic IC50 data is missing from Table 2 and 3 which makes the matter more confusing.
Additional Questions: Originality: Poor
Technical Quality: Poor
Clarity of Presentation: Fair
Importance to Field: Poor
The authors have addressed all necessary safety concerns.: Yes
The length of the article, including the number of figures, is appropriate for its content.: Yes

 So we tried Analytical Chemistry again rejection came 23rd Dec 2012 – good Xmas present.

Journal:  Analytical Chemistry
Manuscript ID: ac-2012-03094v
Title: “The Impact of Dispensing Processes on Biological Assays Determined by Computational and Statistical Analyses”
Author(s): Ekins, Sean; Olechno, Joe; Williams, Antony

Dear Dr. Ekins:

I am reporting on the above manuscript, which you recently submitted for consideration in Analytical Chemistry.

After a careful study of the manuscript and considering the reviewers’ comments, I regret to inform you that I have decided against publication.  The potential usefulness of your work is not in question.  However, in light of the reviewers’ evaluation and comments, I do not believe that publication is justified.  I hope you will find the reviewers’ specific comments helpful in planning future work.  These comments are either included here or, if they were given in the form of a file, will appear at the bottom of the copy of this letter which will appear and be stored in your Author Center.

I appreciate the opportunity to have considered this contribution, and thank you for your interest in Analytical Chemistry.

Kind regards,

John Yates
Associate Editor
Analytical Chemistry

Reviewer(s)’ Comments to Author: Reviewer: 1 Recommendation: Not appropriate subject matter for Analytical Chemistry; recommend the following journal Journal of Biomolecular Screening (http://jbx.sagepub.com/) Comments: I have read the authors’ revisions and continue to believe that the paper lacks the criteria suitable for publication in Analytical Chemistry. Additional Questions: Originality: Fair Technical Quality: Fair Clarity of Presentation: Fair Importance to Field: Poor The authors have addressed all necessary safety concerns.: Yes The length of the article, including the number of figures, is appropriate for its content.: Yes

Reviewer: 2 Recommendation: Publish either as is or subject to minor revisions as indicated. Comments: review attached Additional Questions: Originality: Good Technical Quality: Clarity of Presentation: Good Importance to Field: Good The authors have addressed all necessary safety concerns.: Yes The length of the article, including the number of figures, is appropriate for its content.: Yes

Reviewer:3 Recommendation: Should not be published in Analytical Chemistry. Comments: General comments: 1.    Article addresses concepts at the interface of computational and experimental drug discovery that cannot be adequately summarized in “Letter format”. 2.    The authors state “no previous publication has analyzed or compared such data based on tip-based and acoustic dispensing”. As such this reviewer feels that a detailed (full manuscript) explanation is required for correlating pharmacophore modeling and compound dispensing. Detailed comments: (1)    The authors cite all computational methods used in this research. The use of this analysis to highlight differences between contact and non-contact dispensing is not adequately explained and cannot really be described in a “Letter format” manuscript. (2)    The authors describe highly specialized techniques such as (i) pharmacophore models, (ii) derivation of affinity from these models and (iii) correlation of affinity data with contact vs non-contact dispensing. However they do not provide adequate justification and explanation for their methodology. (3)    The authors use a limited dataset (14 compounds at most) to derive models without an explanation of why their models are correct. (4)    The authors make emphatic statements such as “the result of which is likely to misdirect drug design” that are not justified from their findings on this small dataset. (5)    The authors do not discuss the assays used for tip-based and contactless dispensing. As such they cannot justify the correlation between these datasets, since differences in the assay protocol may give rise to the differential results and not the use of tip vs acoustic dispensing. Additional Questions: Originality: Fair Technical Quality: Poor Clarity of Presentation: Poor Importance to Field: Fair The authors have addressed all necessary safety concerns.: Yes The length of the article, including the number of figures, is appropriate for its content.: No

 reviewer 4. (this one is italicized because I like it)

In this reviewers opinion this paper highlights a critically important factor in the drug
discovery process, namely that the quality of the SAR models built by medicinal chemists is
dependent on the quality of the data generated from the screen. Understanding how the
properties of a compound impact on its potential behavior in a screen is vitally important.
Clearly if compounds have properties which make them difficult to dispense or cause them
to drop out of solution during the assay this will likely lead to an inappropriate estimate of
compound activity in that biological test environment. To maximize the understanding of
SAR space around any pharmacophore it is necessary to have accurate data from as many
exemplar molecules in that space as possible.
The data presented suggests that the physical handling of compounds is important in
ensuring a complete SAR picture is generated. While the data set used in this article is
relatively small, it clearly shows that it is possible to miss biologically relevant chemical
features from design sets when these features adversely impact on the handling properties
of the molecule. In effect library design is biased towards compounds that have good liquid
handling properties and solubility. While ultimately these properties may lead to success in
vivo, biasing library design early in hit identification and lead generation will limit medicinal
chemistry understanding of target engagement at a molecular level.
If the physical handling of compounds can have a profound effect on the IC50 data
generated in an assay due to the chemical properties of the molecule, it brings into question
the integrity of historical screening data sets. A key question would be what percentage of
compounds in any library have the physical properties that might generate erroneous data.
This question is only touched upon in this article and there is some unpublished (anecdotal)
evidence provided at the end of the paper to suggest the scale of the potential issue.
Comments to be addressed by authors:
1. The authors need to remove the word disposable when referencing the tip-based
dispensing. None of the AZ data referenced in this paper was generated with
disposable tip based Tecan Genesis instruments.
2. The authors need to be careful when citing differences between IC50 values. There
will be intrinsic variability between test events and therefore small differences
between IC50s may not be significant. Typical run to run variability in a biochemical
assay could easily result in 3 fold variability between IC50 estimations. In addition it
is more common to use the inverse log of the IC50 value when making comparisons
because the use of the log scale helps to standardize the errors between test events.
I would suggest that for the data presented here anything less than 4 fold difference
in IC50 could just be run to run variability rather than due to the compound handling
process.
3. Citation 14 seems to be inappropriately used on page 3 as it is used to support
statements regarding inhibition of the TK EphB4. The Comley paper is a review of
serial dilution vs direct dilution and is not related to the EphB4 data.
4. Second sentence of the abstract uses “dispensing” too frequently, would read better
if it started, “Data shows IC50 values obtained via tip based serial dilution versus
acoustic dispensing can differ by orders of magnitude…..” The statement as it stands
in the original paper is not only difficult to read but also implies that there is always a
difference between tip-bases IC50s and acoustic IC50s and this is not the case.
5. Sentence 3 page 3 requires softening. The statement that the two liquid handling
techniques generate conflicting results is not always true, only for a sub population of
compounds.

 

Then we tried PLOSONE:Feb 20 2013it was accepted

PONE-D-13-02029
Dispensing Processes Impact Apparent Biological Activity as Determined by Computational and Statistical Analyses
PLOS ONE

Dear Dr. Ekins,

Thank you for submitting your manuscript for review to PLOS ONE. After careful consideration, we feel that your manuscript will likely be suitable for publication if it is revised to address the points below. Therefore, my decision is “Minor Revision.”

We invite you to submit a revised version of the manuscript that addresses the following points:

Please correct the different points asked by the reviewers.

We encourage you to submit your revision within forty-five days of the date of this decision.

When your files are ready, please submit your revision by logging on to http://pone.edmgr.com/ and following the Submissions Needing Revision link. Do not submit a revised manuscript as a new submission. Before uploading, you should proofread your manuscript very closely for mistakes and grammatical errors. Should your manuscript be accepted for publication, you may not have another chance to make corrections as we do not offer pre-publication proofs.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

Please also include a rebuttal letter that responds to each point brought up by the academic editor and reviewer(s). This letter should be uploaded as a Response to Reviewers file.

In addition, please provide a marked-up copy of the changes made from the previous article file as a Manuscript with Tracked Changes file. This can be done using ‘track changes’ in programs such as MS Word and/or highlighting any changes in the new document.

If you choose not to submit a revision, please notify us.

Yours sincerely,

Alexandre G. de Brevern, Ph.D.
Academic Editor
PLOS ONE

Reviewer’s Responses to Questions
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: Yes
Reviewer #2: Yes

Please explain (optional).
Reviewer #1: (No Response)
Reviewer #2: (No Response)

2. Has the statistical analysis been performed appropriately and rigorously?
Reviewer #1: I don’t know
Reviewer #2: Yes

Please explain (optional).
Reviewer #1: Needs further revision
Reviewer #2: (No Response)

3. Does the manuscript adhere to standards in this field for data availability?
Authors must follow field-specific standards for data deposition in publicly available resources and should include accession numbers in the manuscript when relevant. The manuscript should explain what steps have been taken to make data available, particularly in cases where the data cannot be publicly deposited.
Reviewer #1: Yes
Reviewer #2: Yes

Please explain (optional).
Reviewer #1: (No Response)
Reviewer #2: (No Response)

4. 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 below.
Reviewer #1: Yes
Reviewer #2: Yes

Please explain (optional).
Reviewer #1: (No Response)
Reviewer #2: (No Response)

5. Additional Comments to the Author (optional)
Please offer any additional comments here, including concerns about dual publication or research or publication ethics.
Reviewer #1: 1) Write the importance of Pharmacophoric fit values in the respective study.
2) Table 2. Statistical analysis results for statistically significant correlations with IC50. Note the correlation of LogP with 14 molecules using acoustic dispensing and how addition of more compounds results in correlations of LogP and LogD with tip-based dispensing. No correlations were observed for IC50 value against molecular weight, hydrogen bond donors, hydrogen bond acceptors, isoelectric point, polar surface area, molar refractivity.
How the authors consider this as statistically significant correlations with IC50. Though there is very less or no correlation at all between descriptors and activity. Justify the results.
3) How does the study can be carried forward in more general sense of wider applicability. Is this model robust enough for wider class of molecules for w.r.to studied set only??? The range of IC50 values studied. Is this model applicable for identifying less active compounds?
Reviewer #2: (No Response)

6. If you would like your identity to be revealed to the authors, please include your name here (optional).
Your name and review will not be published with the manuscript.
Reviewer #1: (No Response)
Reviewer #2: (No Response)

 SUMMARY

We used all the preceding reviewer comments and each time the manuscript changed. We also had our own ideas of what else to add and remove. Imagine the final paper is bloated compared to the approx 1000 (word) version originally written and the relatively short communication sent to Analytical Chemistry. If I had any advice for scientists in the same position it would be “do not give up! Science is clearly not interested! Analytical Chemistry would not recognize something of relevance if it bit them in the rear.”

As I blogged previously, everything with the final home for the manuscript was going well until the 11th hr when the poop hit the fan on the press release. Just goes to show that sometimes when you think its over, well it isn’t.

 

 

5 comments

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  1. sean says:

    I should add this is another great example of a publishing story with a few twists – earlier in the year I described one regarding the Green Solvents mobile App http://wp.me/p1v91P-4X which we thought would be a great fit for an RSC journal but ended up in an ACS journal. The above PLOS paper also went to an ACS journal which we thought was a good fit, but no joy. I am just grateful to get them accepted, but the amount of time wasted is phenomenal. Basically each of these papers took the best part of a year on the publishing side.

  2. sean says:

    another blog here http://www.collabchem.com/2013/05/06/why-does-this-issue-still-give-me-nightmares/

  3. Ramesh says:

    Greetings,

    Can anyone give me tips on how to make the research manuscript to have high priority rating towards its publication.

    Thank you,
    Ramesh

  4. sean says:

    My commiserations..Sometimes journals do this to triage manuscripts, it could be due to many reasons, poorly written, off topic for journal etc..

    Having an attractive title and abstract helps because most of the time people do not read the whole article at triage stage..

    I do not know what you work on but it might be something that is less fashionable to the high impact journals. Finally, I would recommend you get a friend to read your work who you can trust to give you honest feedback. One other approach is to leave the paper for a few weeks and come back to it imagining you read it for the first time and edit as if a reviewer.

  5. sean says:

    I will be giving a webinar on the PLOS ONE paper July 16 2013

    https://vts.inxpo.com/Launch/QReg.htm?ShowKey=14638

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