Reviewer's report
Title:The clinical characteristics of patients with free perforation in Korean
Crohn's disease: results from the CONNECT study
Version:2Date:5 January 2015
Reviewer: Shun Fung Sze
Reviewer's report:
General comments:
I read your article with interest. There are relatively few studies reporting the
clinical factors associated with free perforation in CD and you have done a very
good job by reviewing the Korean cohort. I presumed all your figures and p-value
on Table 1 is correct (please kindly double check) and appropriate statistical
tests (X2 test and
?t-test) were used for different variables (please seek statistician help if needed).
However, I still noted some reporting figures discrepancy in both your abstract
and the main article as pointed out in my comments below.
You have mentioned almost half of the patients (47.7%) who experienced free
perforation were diagnosed between 1982 – 2004. You said this might be due to
lack of experience in CD management or delayed diagnosis. However, this gives
me another impression that another half of the patients with perforation were
diagnosed between 2005-2008, which means still high or even higher incidence
of perforation in the recent 4 years, and can you give some explanation for this?
It would be very interesting if possible that you further analyze the difference
between the two time periods especially after the introduction of biologics.
I think Figure 1 is unnecessary in this article and can be omitted. Below I have
made my comments according to each paragraph of your article.
(1) Abstract
Minor Essential Revisions:
line 9: Results: A total of ?1346 pateitns instead of 1382
line 12: (p=0.004) instead of 0.003
line 17 (4.5%) instead of 4.6% and (p<0.001) instead of p=0.001
(2) Introduction
Major Compulsory Revisions:
too lengthy, please try to make your introduction more concise
Minor Essential Revisions:
line 4: mimics (not mimicks)
line 9-11: ... from 0.05 per 100,000 (no need inhabitants) between 1986 and
1990 to 1.34 per 100,000 between 2001 and 2005. While the incidence of CD
remains lower than that in western (not westernized) countries, its recent
increase in Asian countries, including ...
line 13: ... western countries...
line 14: ... between gender, the locations of involved segments, and ....
line 16: ... western countries...
line 17: ... have been conducted to investigate free perforation...
line 18: ... aim of this study is to determine ...
(3) Materials and Methods - Study population
Major Compulsory Revisions:
A total of ?1382 (should it be 1346 patients which was quoted in the result)
Discretionary Revisions
It would be better to mention how this CONNECT study cohort is representative
of the Korean population (does it include all CD patients in Korea?)
(4) Materials and Methods - Clinical characteristics
Minor Essential Revisions:
line 18: ...including the time of symptom onset, ...
line 21: prognosis (not prognoses) or you can use the term “clinical outcome”
line 22 ... and result in mortality (instead of ?all-cause death)
(5) Materials and Methods - Statistical analysis
Major Compulsory Revisions:
a) Continuous variables are described as means (not medians) and standard
deviations (I would also suggest you adding the use median and range for some
of the variables e.g. time from symptom onset to diagnosis)
b) The differences between the groups were assessed using X2 test - should be
categorical variables only. How about continuous variables? Are they assessed
with t-test? You have four continuous variables, namely age at diagnosis, time
from symptom onset to diagnosis, CDAI at diagnosis and number of CD related
hospitalization
c) Do you mean by: Multivariate logistic regression analysis was used to examine
the association of the clinical characteristics of CD patients between those with
and without free perforation?
(6) Results - Incidence of free perforation
Minor Essential Revisions:
line 17: 1346 patients (not consistent with 1382 patients mentioned in Study and
Method
(7) Results - Clinical characteristics
Major Compulsory Revisions:
line 14: I would consider Figure 1 unnecessary
line 15: (Table 1) should be changed to a sentence: Table 1 shows the
comparison of characteristics between free perforation group and non-perforated
group in our Crohn's disease cohort
Discretionary Revisions
a) line 24-25: Mean follow-up periods were 125.0 for the free perforation group
and 103.7 months for the non-perforated group (p=0.003). - Please consider
explain this significant p value if you decide to quote it, otherwise you can omit
this p-value.
b) Mean age and Mean time from the first symptom to diagnosis - Please
consider quoting the Median and range instead of the mean +/- SD
c) Disease behavior at CD diagnosis - B1 and B3 got a p value of <0.001. You
did not mention this on this section. It might be difficult to explain this.
(8) Results - Risk factors associated with free perforation
Major Compulsory Revisions:
You mentioned there were no significant associations with medications, but I
noted that antibiotics use had a p-value of 0.033 (that is <0.05). Did you miss
explaining this?
Discretionary Revisions:
Again, why not include the use of antibiotics in the multivariate logistic regression
analysis
(9) Results- Prognosis of CD patients with free perforation
Discretionary Revisions:
Line 12: died in the perforation group (not dying)…died in the non-perforated
group
(10) Discussion
Major compulsory revisions:
(a) page 9 line 10-16: I think this paragraph should be considered as “limitations
of the study”. However, in your study, you exclude abscess ruptures (but also
excluded in other studies) and exclude secondary perforations (?are you sure
that they are included in other studies) and exclude perforations not documented
accurately (?are you sure they are not excluded in other studies). This paragraph
is a bit confusing. You should consider delete this paragraph if you cannot
explain your reasoning more clearly.
(b) page 10 line 8-10: ... some drugs, including steroids and anti-TNF agents,
increase the risk of free perforation by obscuring clinical signs and by preventing
the closure of perforations [9-12,19-21]... All these references 9-12,19-21 were
written before the era of anti-TNF agents, so I think that anti-TNF should not be
mentioned in this sentence.
(c) page 11 line 1-2: ... free perforation group (4.5%)......(RR=7.72, p<0.001)
Minor essential Revisions:
page 8 line 19: ... western countries...
page 9 line 2-3: ... 7.4% of the patients. The Japanese study also reported that ...
page 9 line 8: ...might be associated with diagnostic difficulties that relate ...
page 9 line 20: ... These results had led us to consider ...
page 9 line 24: ..., but this difference was not statistically significant (p=0.074).
page 11 line 7-9: ... However, with improvement in surgical procedures and the
availability of newer medication including biologics, this may lead to more
successful treatment of CD.
page 11 line 17: ... western countries...
Discretionary Revisions:
Would you consider subgroup analysis only on those patients diagnosed CD
AFTER infliximab become available in the market to see whether anti-TNF is
associated with more perforation?
(11) Table 1
Major compulsory revision:
Disease Location at diagnosis with CD – overall P-value 0.048
Disease Behaviour at diagnosis with CD – overall P-value <0.001
These two p-values should be deleted unless you are going to explain them
Discretionary Revision:
I would suggest you to add one more row on Age at diagnosis >=30 with the
number of patients in each group together with its p-value by X2 test
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Needs some language corrections before being
published
Statistical review: Yes, and I have assessed the statistics in my report.
Declaration of competing interests:
I declare that I have no competing interests
Reviewer's report
Title:The clinical characteristics of patients with free perforation in Korean
Crohn's disease: results from the CONNECT study
Version:2Date:5 January 2015
Reviewer: Shun Fung Sze
Reviewer's report:
General comments:
I read your article with interest. There are relatively few studies reporting the
clinical factors associated with free perforation in CD and you have done a very
good job by reviewing the Korean cohort. I presumed all your figures and p-value
on Table 1 is correct (please kindly double check) and appropriate statistical
tests (X2 test and
?t-test) were used for different variables (please seek statistician help if needed).
However, I still noted some reporting figures discrepancy in both your abstract
and the main article as pointed out in my comments below.
You have mentioned almost half of the patients (47.7%) who experienced free
perforation were diagnosed between 1982 – 2004. You said this might be due to
lack of experience in CD management or delayed diagnosis. However, this gives
me another impression that another half of the patients with perforation were
diagnosed between 2005-2008, which means still high or even higher incidence
of perforation in the recent 4 years, and can you give some explanation for this?
It would be very interesting if possible that you further analyze the difference
between the two time periods especially after the introduction of biologics.
I think Figure 1 is unnecessary in this article and can be omitted. Below I have
made my comments according to each paragraph of your article.
(1) Abstract
Minor Essential Revisions:
line 9: Results: A total of ?1346 pateitns instead of 1382
line 12: (p=0.004) instead of 0.003
line 17 (4.5%) instead of 4.6% and (p<0.001) instead of p=0.001
(2) Introduction
Major Compulsory Revisions:
too lengthy, please try to make your introduction more concise
Minor Essential Revisions:
line 4: mimics (not mimicks)
line 9-11: ... from 0.05 per 100,000 (no need inhabitants) between 1986 and
1990 to 1.34 per 100,000 between 2001 and 2005. While the incidence of CD
remains lower than that in western (not westernized) countries, its recent
increase in Asian countries, including ...
line 13: ... western countries...
line 14: ... between gender, the locations of involved segments, and ....
line 16: ... western countries...
line 17: ... have been conducted to investigate free perforation...
line 18: ... aim of this study is to determine ...
(3) Materials and Methods - Study population
Major Compulsory Revisions:
A total of ?1382 (should it be 1346 patients which was quoted in the result)
Discretionary Revisions
It would be better to mention how this CONNECT study cohort is representative
of the Korean population (does it include all CD patients in Korea?)
(4) Materials and Methods - Clinical characteristics
Minor Essential Revisions:
line 18: ...including the time of symptom onset, ...
line 21: prognosis (not prognoses) or you can use the term “clinical outcome”
line 22 ... and result in mortality (instead of ?all-cause death)
(5) Materials and Methods - Statistical analysis
Major Compulsory Revisions:
a) Continuous variables are described as means (not medians) and standard
deviations (I would also suggest you adding the use median and range for some
of the variables e.g. time from symptom onset to diagnosis)
b) The differences between the groups were assessed using X2 test - should be
categorical variables only. How about continuous variables? Are they assessed
with t-test? You have four continuous variables, namely age at diagnosis, time
from symptom onset to diagnosis, CDAI at diagnosis and number of CD related
hospitalization
c) Do you mean by: Multivariate logistic regression analysis was used to examine
the association of the clinical characteristics of CD patients between those with
and without free perforation?
(6) Results - Incidence of free perforation
Minor Essential Revisions:
line 17: 1346 patients (not consistent with 1382 patients mentioned in Study and
Method
(7) Results - Clinical characteristics
Major Compulsory Revisions:
line 14: I would consider Figure 1 unnecessary
line 15: (Table 1) should be changed to a sentence: Table 1 shows the
comparison of characteristics between free perforation group and non-perforated
group in our Crohn's disease cohort
Discretionary Revisions
a) line 24-25: Mean follow-up periods were 125.0 for the free perforation group
and 103.7 months for the non-perforated group (p=0.003). - Please consider
explain this significant p value if you decide to quote it, otherwise you can omit
this p-value.
b) Mean age and Mean time from the first symptom to diagnosis - Please
consider quoting the Median and range instead of the mean +/- SD
c) Disease behavior at CD diagnosis - B1 and B3 got a p value of <0.001. You
did not mention this on this section. It might be difficult to explain this.
(8) Results - Risk factors associated with free perforation
Major Compulsory Revisions:
You mentioned there were no significant associations with medications, but I
noted that antibiotics use had a p-value of 0.033 (that is <0.05). Did you miss
explaining this?
Discretionary Revisions:
Again, why not include the use of antibiotics in the multivariate logistic regression
analysis
(9) Results- Prognosis of CD patients with free perforation
Discretionary Revisions:
Line 12: died in the perforation group (not dying)…died in the non-perforated
group
(10) Discussion
Major compulsory revisions:
(a) page 9 line 10-16: I think this paragraph should be considered as “limitations
of the study”. However, in your study, you exclude abscess ruptures (but also
excluded in other studies) and exclude secondary perforations (?are you sure
that they are included in other studies) and exclude perforations not documented
accurately (?are you sure they are not excluded in other studies). This paragraph
is a bit confusing. You should consider delete this paragraph if you cannot
explain your reasoning more clearly.
(b) page 10 line 8-10: ... some drugs, including steroids and anti-TNF agents,
increase the risk of free perforation by obscuring clinical signs and by preventing
the closure of perforations [9-12,19-21]... All these references 9-12,19-21 were
written before the era of anti-TNF agents, so I think that anti-TNF should not be
mentioned in this sentence.
(c) page 11 line 1-2: ... free perforation group (4.5%)......(RR=7.72, p<0.001)
Minor essential Revisions:
page 8 line 19: ... western countries...
page 9 line 2-3: ... 7.4% of the patients. The Japanese study also reported that ...
page 9 line 8: ...might be associated with diagnostic difficulties that relate ...
page 9 line 20: ... These results had led us to consider ...
page 9 line 24: ..., but this difference was not statistically significant (p=0.074).
page 11 line 7-9: ... However, with improvement in surgical procedures and the
availability of newer medication including biologics, this may lead to more
successful treatment of CD.
page 11 line 17: ... western countries...
Discretionary Revisions:
Would you consider subgroup analysis only on those patients diagnosed CD
AFTER infliximab become available in the market to see whether anti-TNF is
associated with more perforation?
(11) Table 1
Major compulsory revision:
Disease Location at diagnosis with CD – overall P-value 0.048
Disease Behaviour at diagnosis with CD – overall P-value <0.001
These two p-values should be deleted unless you are going to explain them
Discretionary Revision:
I would suggest you to add one more row on Age at diagnosis >=30 with the
number of patients in each group together with its p-value by X2 test
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Needs some language corrections before being
published
Statistical review: Yes, and I have assessed the statistics in my report.
Declaration of competing interests:
I declare that I have no competing interests
Please review this paper.
user
Reviewer's report
Title:The clinical characteristics of patients with free perforation in Korean
Crohn's disease: results from the CONNECT study
Version:2Date:5 January 2015
Reviewer: Shun Fung Sze
Reviewer's report:
General comments:
I read your article with interest. There are relatively few studies reporting the
clinical factors associated with free perforation in CD and you have done a very
good job by reviewing the Korean cohort. I presumed all your figures and p-value
on Table 1 is correct (please kindly double check) and appropriate statistical
tests (X2 test and
?t-test) were used for different variables (please seek statistician help if needed).
However, I still noted some reporting figures discrepancy in both your abstract
and the main article as pointed out in my comments below.
You have mentioned almost half of the patients (47.7%) who experienced free
perforation were diagnosed between 1982 – 2004. You said this might be due to
lack of experience in CD management or delayed diagnosis. However, this gives
me another impression that another half of the patients with perforation were
diagnosed between 2005-2008, which means still high or even higher incidence
of perforation in the recent 4 years, and can you give some explanation for this?
It would be very interesting if possible that you further analyze the difference
between the two time periods especially after the introduction of biologics.
I think Figure 1 is unnecessary in this article and can be omitted. Below I have
made my comments according to each paragraph of your article.
(1) Abstract
Minor Essential Revisions:
line 9: Results: A total of ?1346 pateitns instead of 1382
line 12: (p=0.004) instead of 0.003
line 17 (4.5%) instead of 4.6% and (p<0.001) instead of p=0.001
(2) Introduction
Major Compulsory Revisions:
too lengthy, please try to make your introduction more concise
Minor Essential Revisions:
line 4: mimics (not mimicks)
line 9-11: ... from 0.05 per 100,000 (no need inhabitants) between 1986 and
1990 to 1.34 per 100,000 between 2001 and 2005. While the incidence of CD
remains lower than that in western (not westernized) countries, its recent
increase in Asian countries, including ...
line 13: ... western countries...
line 14: ... between gender, the locations of involved segments, and ....
line 16: ... western countries...
line 17: ... have been conducted to investigate free perforation...
line 18: ... aim of this study is to determine ...
(3) Materials and Methods - Study population
Major Compulsory Revisions:
A total of ?1382 (should it be 1346 patients which was quoted in the result)
Discretionary Revisions
It would be better to mention how this CONNECT study cohort is representative
of the Korean population (does it include all CD patients in Korea?)
(4) Materials and Methods - Clinical characteristics
Minor Essential Revisions:
line 18: ...including the time of symptom onset, ...
line 21: prognosis (not prognoses) or you can use the term “clinical outcome”
line 22 ... and result in mortality (instead of ?all-cause death)
(5) Materials and Methods - Statistical analysis
Major Compulsory Revisions:
a) Continuous variables are described as means (not medians) and standard
deviations (I would also suggest you adding the use median and range for some
of the variables e.g. time from symptom onset to diagnosis)
b) The differences between the groups were assessed using X2 test - should be
categorical variables only. How about continuous variables? Are they assessed
with t-test? You have four continuous variables, namely age at diagnosis, time
from symptom onset to diagnosis, CDAI at diagnosis and number of CD related
hospitalization
c) Do you mean by: Multivariate logistic regression analysis was used to examine
the association of the clinical characteristics of CD patients between those with
and without free perforation?
(6) Results - Incidence of free perforation
Minor Essential Revisions:
line 17: 1346 patients (not consistent with 1382 patients mentioned in Study and
Method
(7) Results - Clinical characteristics
Major Compulsory Revisions:
line 14: I would consider Figure 1 unnecessary
line 15: (Table 1) should be changed to a sentence: Table 1 shows the
comparison of characteristics between free perforation group and non-perforated
group in our Crohn's disease cohort
Discretionary Revisions
a) line 24-25: Mean follow-up periods were 125.0 for the free perforation group
and 103.7 months for the non-perforated group (p=0.003). - Please consider
explain this significant p value if you decide to quote it, otherwise you can omit
this p-value.
b) Mean age and Mean time from the first symptom to diagnosis - Please
consider quoting the Median and range instead of the mean +/- SD
c) Disease behavior at CD diagnosis - B1 and B3 got a p value of <0.001. You
did not mention this on this section. It might be difficult to explain this.
(8) Results - Risk factors associated with free perforation
Major Compulsory Revisions:
You mentioned there were no significant associations with medications, but I
noted that antibiotics use had a p-value of 0.033 (that is <0.05). Did you miss
explaining this?
Discretionary Revisions:
Again, why not include the use of antibiotics in the multivariate logistic regression
analysis
(9) Results- Prognosis of CD patients with free perforation
Discretionary Revisions:
Line 12: died in the perforation group (not dying)…died in the non-perforated
group
(10) Discussion
Major compulsory revisions:
(a) page 9 line 10-16: I think this paragraph should be considered as “limitations
of the study”. However, in your study, you exclude abscess ruptures (but also
excluded in other studies) and exclude secondary perforations (?are you sure
that they are included in other studies) and exclude perforations not documented
accurately (?are you sure they are not excluded in other studies). This paragraph
is a bit confusing. You should consider delete this paragraph if you cannot
explain your reasoning more clearly.
(b) page 10 line 8-10: ... some drugs, including steroids and anti-TNF agents,
increase the risk of free perforation by obscuring clinical signs and by preventing
the closure of perforations [9-12,19-21]... All these references 9-12,19-21 were
written before the era of anti-TNF agents, so I think that anti-TNF should not be
mentioned in this sentence.
(c) page 11 line 1-2: ... free perforation group (4.5%)......(RR=7.72, p<0.001)
Minor essential Revisions:
page 8 line 19: ... western countries...
page 9 line 2-3: ... 7.4% of the patients. The Japanese study also reported that ...
page 9 line 8: ...might be associated with diagnostic difficulties that relate ...
page 9 line 20: ... These results had led us to consider ...
page 9 line 24: ..., but this difference was not statistically significant (p=0.074).
page 11 line 7-9: ... However, with improvement in surgical procedures and the
availability of newer medication including biologics, this may lead to more
successful treatment of CD.
page 11 line 17: ... western countries...
Discretionary Revisions:
Would you consider subgroup analysis only on those patients diagnosed CD
AFTER infliximab become available in the market to see whether anti-TNF is
associated with more perforation?
(11) Table 1
Major compulsory revision:
Disease Location at diagnosis with CD – overall P-value 0.048
Disease Behaviour at diagnosis with CD – overall P-value <0.001
These two p-values should be deleted unless you are going to explain them
Discretionary Revision:
I would suggest you to add one more row on Age at diagnosis >=30 with the
number of patients in each group together with its p-value by X2 test
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Needs some language corrections before being
published
Statistical review: Yes, and I have assessed the statistics in my report.
Declaration of competing interests:
I declare that I have no competing interests
assistant