Review for 10.1186/s12876-021-01740-6 (2021)

Title: Distinct clinical phenotypes for Crohn’s disease derived from patient surveys
Version: 2 Date: 02 Feb 2021
Reviewer's report:
Thank you for giving me the opportunity to review this paper, which aims to evaluate the degree
to which patient-reported survey health and medical data suggests disease sub-phenotypes.
The paper has an interesting aim and I find the background and reasoning for the paper well-
written. However, the methods and results are very unstructured and confusing. The methods
and results sections include repetitions and have sections that are mixed up. Not all analyses
corresponding to the results are explained in the methods. This makes it difficult to follow the
method of the study and to understand the results. The discussion is overall well-written but also
needs revision. Below are my specific comments to the paper.
Background:
1) The aim of the paper is described two places. Page 3, in the middle and page 5, in last
paragraph. Please do not repeat the aims and state the aim only ones.
Methods:
1) The first line in the methods, where the authors note that the method section was moved in
front of the result section, should be removed. In addition, the paper has not been adjusted after
the sections were switched, since some definitions appear after the concept has been mentioned
the first time. (for instance the CD-like subtype. It is mentioned first time at page 8, but defined
at page 10).
2) In the section “Questionnaire design”, the authors state “We explore the usefulness of this
questionnaires in phenotype classification with an aim to learn how to optimize questionnaire
design.” This is an aim and should be moved to the background or deleted.
3) The authors needs to give a more detailed presentation of the questionnaire in the beginning of
the method section. As a reader, I miss an overview of the questions that are in the questionnaire.
I suggest the authors to include a small description of the questions in each section of the
questionnaire.
4) The section “Select of phenotypes from patient questionnaire” is a mixture of questionnaire
selection and the patient selection. I recommend the authors to separate these two information
and provide a flowchart for the patient selection as they did it for the question selection.
5) In the section “Identify disease subtypes and analyze features” Table 5 provides results and
this should be moved to the result section.
6) In the section “Identify genotyping signature”, the authors mention the CD-like and CD-like
UC subtypes but these were not defined previously.
Results:
1) The first paragraph in the “Phenotypic question selection from patient questionnaires” section
gives a description of the questionnaire and should be moved to the method section. The last
line in this section was already mentioned in the method section and should be removed.
2) The second and third paragraph in the “Phenotypic question selection from patient
questionnaires” is essentially a repetition of the section “Select phenotypes from patient
questionnaire” in the method section. It confuses me why the paragraphs are repeated here. They
should be removed.
3) In the section “Classification of disease subtypes” the authors state “So immediately we see
that standard clinical labels, particularly for CD, do not correspond to our clustering. While we
did not include clinical disease labels (CD or UC) in the original clustering, we wondered why
CD labeled patients were separated into these two groups. We therefore did a subanalysis of the
two CD cohorts searching for differences.” The result section should only include the results
of the study and no subjective statements from the authors. This part should be moved to the
discussion.
4) In the section “Classification of disease subtypes” the authors state “The phenotypes are
significantly different (Table 2): surgery_any, peripheral_arthritis, axial_arthritis, osteoporosis,
osteopenia, skin, fissure, abdominal_abcess, perianal_abcess and stricture.” I recommend the
authors to not use the variable names but to explain the reader what these phenotypes mean.
5) In the section “Associations between external evidence, drug response and disease subtypes”
the authors include paragraphs that should be in the discussion. I want to remember the authors
that the result section should only include the results in an objective manner and the results
should not be interpreted in the result section but in the discussion section. Following paragraphs
should be moved to the discussion;
5a) “…suggesting that smoking may be associated with more severe CD symptoms”.
5b) “Cigarette smoking is a confirmed risk factor involved in the pathogenesis of Crohn’s
disease, but seems to be a disease aggravating rather than a disease-causing factor. It has been
linked to disease progression and unfavorable disease outcome across the world. In fact, smokers
are more likely to develop fistulae”.
5c) Previous studies suggest a greater rate of mother-to-child transmission in CD patients,
suggesting a potential female sex-specific epigenetic inheritance pattern for CD. The CD-like
CD subtype that we identified based on patients’ own observations may be relevant to family-
specific risk of severe CD.
6) In the last paragraph in the section “Associations between external evidence, drug response
and disease subtypes”:
6a) The analysis looking at the association between smoking and the subtypes was not described
in the method section.
6b) I recommend the authors to include point estimates.
7) In the section “Detection of genotyping signature for CD subtypes” the authors state “ASH1L
has been previously shown to suppress inflammation by decreasing IL6 and TNF production
and has been shown to be significantly downregulated in UC28…..”. This should be moved to
the discussion. In the same section the paragraph starting with “RAB1A has been shown to be
dysregulated in histologically normal lung tissue in smokers….” should also be moved to the
discussion.
Discussion
1) The paragraph, which starts with “We processed the two conditional questions as below….”
has been included in the paper several times (!?). This paragraph does not belong to the
discussion and should be removed.
General comments
1) Please align the citation in the text. Sometimes the citation is superscripted and sometimes not.
2) The text needs language correction. See for instance legend for table 5.
3) Table 4 should be explained in more detail. What does “positivie:negative” mean in the last
column?
4) I recommend the authors to align the method section and the result section so all analysis
corresponding to the results are explained in the method section.