Title: Differential diagnosis of Crohn's disease and intestinal tuberculosis: development and
assessment of a nomogram prediction model
Version: 2 Date: 27 Jun 2022
Reviewer's report:
This is a very nice submission addressing an important diagnostic challenge in many countries,
thank you for the opportunity to review. This submission outlines the author’s comprehensive
evaluation, of a retrospective cohort of both confirmed Crohn’s disease (CD) patients and those
with tuberculosis (TB) to identify distinguishing, predictive parameters, which were combined
into a predictive score/ index. This particular study includes a wider array of important diagnostic
tests/ predictors than previously published similar indices.
I have highlighted a few spelling/ grammatical English language errors in the word document.
Please insert at least page numbers to help with feedback and editing. Please also do a spell
check.
The abstract is clear. I do however suggest including the total number of patients reviewed for
each disease state in addition to your predictive findings.
In the intro – the statement “has high differential diagnosis value” – would this be better phrased
simply high diagnostic value – or accurate diagnostic value?
I am not sure I would even suggest or include ASCA as a serologic diagnostic test – this has
zero value and is not routinely used in clinical practice. It absolutely has zero contribution to the
diagnosis of CD is not considered standard of care, nor recommended by international guidelines
(e.g. ECCO).
The use of the term “differential diagnosis indexes” is also a bit confusing – how about lack
of diagnostic accuracy?
Clinical “maneuverability? Is also not clear – how about utility? Or easy application/ use?
In the purpose final paragraph/ sentence – is it one index or more than one? You are using more
than one factor/ element but clinical manifestations do are not an “index” -  are you
“synthesizing the valuable diagnostic indices” – or are you creating an index out of a number
of contributing factors?
Other than these minor points, the intro is well written and communicates the challenges you
are addressing well.
Methods
Why are prior intestinal resections excluded?
Although very detailed and outlined clearly, I suggest each of the categories of elements you
are collecting be better presented in a table? It is a long list presented in the methods. I also
wonder if the order within the methods may be better arranged to start with the study design
and then the patients?
It might be helpful to define T-SPOT, beyond T cell spot test? How is this test performed and
relative to quantiferon, is this a readily available test? Routinely used? Inexpensive?
Your approach to bootstrapping validation uses the same data set correct? This would be
considered a flawed method of validation and will result in over estimation of validity -
validation generally must occur within a separate cohort.
Results
The flow chart in Supplementary Figure 1. I suggest might be best placed in the methods section
(this sentence included).
Not surprisingly, the clinical symptoms were not discerning. Did you consider including
additional demographic factors such as income, known TB contacts in the household/ close
contact, family history of IBD vs TB, environment exposures including employment? Often it’s
the clinical history that generates the pre-test probability.
Interesting no commentary on lymph nodes  on imaging– number or character as a potential
differentiator in TB vs CD.
Do you measure quantiferon at all? This may be an important test that can be helpful for
equivocal TB skin tests.
Discussion
Again, in the first paragraph – you sate the “differential diagnosis of these two diseases” has
become … it not the differential diagnosis that is the challenge, it is differentiating these diseases
in a timely and accurate manner. This phrase again is used throughout the paper and I suggest
changing it.
You state in your discussion that you screened demographics – but in the most basic way: gender
and age only. No historical risk factors for TB. It is interesting, in real life, its the PRE test
probability (based on comprehensive clinical history) that really frames these tests and their
accuracy. When you suspect TB, you may expedite certain aspects of the battery of tests over
others for example. You really don't address this in your discussion.
The discussion nicely outlines extant literature and scores/ prediction indices. The paragraph
above the ‘strengths’ repeats/ concludes again all of your findings and is a repeat – I suggest
taking it out or at least leaving some/ shortening it for the conclusion as the discussion is quite
long.
One addition weakness you might consider – agree with all of your strengths, is the retrospective
model.  In addition to larger studies – these should be prospective in nature to understand utility.
In the end, this index has some differences compared to existing indices however,  unfortunately,
similar challenges remain in a) timely access to these  diagnostic tests b) characteristic or
stereotypic manifestations e.g. cobblestoning and granuloma.
In the end, you do demonstrate slightly higher accuracy but a very complex and exhaustive set
of diagnostic tests with hopes at least some of them are going to be 'typical'.
Title: Differential diagnosis of Crohn's disease and intestinal tuberculosis: development and
assessment of a nomogram prediction model
Version: 2 Date: 27 Jun 2022
Reviewer's report:
This is a very nice submission addressing an important diagnostic challenge in many countries,
thank you for the opportunity to review. This submission outlines the author’s comprehensive
evaluation, of a retrospective cohort of both confirmed Crohn’s disease (CD) patients and those
with tuberculosis (TB) to identify distinguishing, predictive parameters, which were combined
into a predictive score/ index. This particular study includes a wider array of important diagnostic
tests/ predictors than previously published similar indices.
I have highlighted a few spelling/ grammatical English language errors in the word document.
Please insert at least page numbers to help with feedback and editing. Please also do a spell
check.
The abstract is clear. I do however suggest including the total number of patients reviewed for
each disease state in addition to your predictive findings.
In the intro – the statement “has high differential diagnosis value” – would this be better phrased
simply high diagnostic value – or accurate diagnostic value?
I am not sure I would even suggest or include ASCA as a serologic diagnostic test – this has
zero value and is not routinely used in clinical practice. It absolutely has zero contribution to the
diagnosis of CD is not considered standard of care, nor recommended by international guidelines
(e.g. ECCO).
The use of the term “differential diagnosis indexes” is also a bit confusing – how about lack
of diagnostic accuracy?
Clinical “maneuverability? Is also not clear – how about utility? Or easy application/ use?
In the purpose final paragraph/ sentence – is it one index or more than one? You are using more
than one factor/ element but clinical manifestations do are not an “index” -  are you
“synthesizing the valuable diagnostic indices” – or are you creating an index out of a number
of contributing factors?
Other than these minor points, the intro is well written and communicates the challenges you
are addressing well.
Methods
Why are prior intestinal resections excluded?
Although very detailed and outlined clearly, I suggest each of the categories of elements you
are collecting be better presented in a table? It is a long list presented in the methods. I also
wonder if the order within the methods may be better arranged to start with the study design
and then the patients?
It might be helpful to define T-SPOT, beyond T cell spot test? How is this test performed and
relative to quantiferon, is this a readily available test? Routinely used? Inexpensive?
Your approach to bootstrapping validation uses the same data set correct? This would be
considered a flawed method of validation and will result in over estimation of validity -
validation generally must occur within a separate cohort.
Results
The flow chart in Supplementary Figure 1. I suggest might be best placed in the methods section
(this sentence included).
Not surprisingly, the clinical symptoms were not discerning. Did you consider including
additional demographic factors such as income, known TB contacts in the household/ close
contact, family history of IBD vs TB, environment exposures including employment? Often it’s
the clinical history that generates the pre-test probability.
Interesting no commentary on lymph nodes  on imaging– number or character as a potential
differentiator in TB vs CD.
Do you measure quantiferon at all? This may be an important test that can be helpful for
equivocal TB skin tests.
Discussion
Again, in the first paragraph – you sate the “differential diagnosis of these two diseases” has
become … it not the differential diagnosis that is the challenge, it is differentiating these diseases
in a timely and accurate manner. This phrase again is used throughout the paper and I suggest
changing it.
You state in your discussion that you screened demographics – but in the most basic way: gender
and age only. No historical risk factors for TB. It is interesting, in real life, its the PRE test
probability (based on comprehensive clinical history) that really frames these tests and their
accuracy. When you suspect TB, you may expedite certain aspects of the battery of tests over
others for example. You really don't address this in your discussion.
The discussion nicely outlines extant literature and scores/ prediction indices. The paragraph
above the ‘strengths’ repeats/ concludes again all of your findings and is a repeat – I suggest
taking it out or at least leaving some/ shortening it for the conclusion as the discussion is quite
long.
One addition weakness you might consider – agree with all of your strengths, is the retrospective
model.  In addition to larger studies – these should be prospective in nature to understand utility.
In the end, this index has some differences compared to existing indices however,  unfortunately,
similar challenges remain in a) timely access to these  diagnostic tests b) characteristic or
stereotypic manifestations e.g. cobblestoning and granuloma.
In the end, you do demonstrate slightly higher accuracy but a very complex and exhaustive set
of diagnostic tests with hopes at least some of them are going to be 'typical'.
Please review this paper.
user
Title: Differential diagnosis of Crohn's disease and intestinal tuberculosis: development and
assessment of a nomogram prediction model
Version: 2 Date: 27 Jun 2022
Reviewer's report:
This is a very nice submission addressing an important diagnostic challenge in many countries,
thank you for the opportunity to review. This submission outlines the author’s comprehensive
evaluation, of a retrospective cohort of both confirmed Crohn’s disease (CD) patients and those
with tuberculosis (TB) to identify distinguishing, predictive parameters, which were combined
into a predictive score/ index. This particular study includes a wider array of important diagnostic
tests/ predictors than previously published similar indices.
I have highlighted a few spelling/ grammatical English language errors in the word document.
Please insert at least page numbers to help with feedback and editing. Please also do a spell
check.
The abstract is clear. I do however suggest including the total number of patients reviewed for
each disease state in addition to your predictive findings.
In the intro – the statement “has high differential diagnosis value” – would this be better phrased
simply high diagnostic value – or accurate diagnostic value?
I am not sure I would even suggest or include ASCA as a serologic diagnostic test – this has
zero value and is not routinely used in clinical practice. It absolutely has zero contribution to the
diagnosis of CD is not considered standard of care, nor recommended by international guidelines
(e.g. ECCO).
The use of the term “differential diagnosis indexes” is also a bit confusing – how about lack
of diagnostic accuracy?
Clinical “maneuverability? Is also not clear – how about utility? Or easy application/ use?
In the purpose final paragraph/ sentence – is it one index or more than one? You are using more
than one factor/ element but clinical manifestations do are not an “index” -  are you
“synthesizing the valuable diagnostic indices” – or are you creating an index out of a number
of contributing factors?
Other than these minor points, the intro is well written and communicates the challenges you
are addressing well.
Methods
Why are prior intestinal resections excluded?
Although very detailed and outlined clearly, I suggest each of the categories of elements you
are collecting be better presented in a table? It is a long list presented in the methods. I also
wonder if the order within the methods may be better arranged to start with the study design
and then the patients?
It might be helpful to define T-SPOT, beyond T cell spot test? How is this test performed and
relative to quantiferon, is this a readily available test? Routinely used? Inexpensive?
Your approach to bootstrapping validation uses the same data set correct? This would be
considered a flawed method of validation and will result in over estimation of validity -
validation generally must occur within a separate cohort.
Results
The flow chart in Supplementary Figure 1. I suggest might be best placed in the methods section
(this sentence included).
Not surprisingly, the clinical symptoms were not discerning. Did you consider including
additional demographic factors such as income, known TB contacts in the household/ close
contact, family history of IBD vs TB, environment exposures including employment? Often it’s
the clinical history that generates the pre-test probability.
Interesting no commentary on lymph nodes  on imaging– number or character as a potential
differentiator in TB vs CD.
Do you measure quantiferon at all? This may be an important test that can be helpful for
equivocal TB skin tests.
Discussion
Again, in the first paragraph – you sate the “differential diagnosis of these two diseases” has
become … it not the differential diagnosis that is the challenge, it is differentiating these diseases
in a timely and accurate manner. This phrase again is used throughout the paper and I suggest
changing it.
You state in your discussion that you screened demographics – but in the most basic way: gender
and age only. No historical risk factors for TB. It is interesting, in real life, its the PRE test
probability (based on comprehensive clinical history) that really frames these tests and their
accuracy. When you suspect TB, you may expedite certain aspects of the battery of tests over
others for example. You really don't address this in your discussion.
The discussion nicely outlines extant literature and scores/ prediction indices. The paragraph
above the ‘strengths’ repeats/ concludes again all of your findings and is a repeat – I suggest
taking it out or at least leaving some/ shortening it for the conclusion as the discussion is quite
long.
One addition weakness you might consider – agree with all of your strengths, is the retrospective
model.  In addition to larger studies – these should be prospective in nature to understand utility.
In the end, this index has some differences compared to existing indices however,  unfortunately,
similar challenges remain in a) timely access to these  diagnostic tests b) characteristic or
stereotypic manifestations e.g. cobblestoning and granuloma.
In the end, you do demonstrate slightly higher accuracy but a very complex and exhaustive set
of diagnostic tests with hopes at least some of them are going to be 'typical'.
assistant