Reviewer ’s report  
 
Title: Risks of hospitalization and drug consumption in children and young adults with 
diagnosed  celiac disease and the role of maternal education: a population -based matched birth 
cohort study.  
 
 
Version: 0 Date: 25 Nov 2015  
 
 
Reviewer: Olof Sandstr öm 
 
 
Reviewer's report:  
 
"Risks of hospitalization and drug consumption in children and young adults with diagno sed 
celiac disease and the role of maternal education: a population -based matched birth cohort study" 
by Canova et al (BMGE -D-15-00217)  
 
This is a registry -based study conducted in the region of Friuli -Venezia Giulia in Italy. It starts 
with a birth regist ry with information on maternal education that is linked to a national hospital 
discharge registry and a prescription registry (national?). CD diagnosis is based on ICD9 
diagnosis from hospital discharge registry, pathology reports or copayment data. To ea ch CD 
case up to 5 controls was selected, matched on maternal education, and sex and age of the CD 
case. The objectives are to study the effect of CD on the use of health -care resources, the 
persistence of such a phenomena and if the maternal level of educ ations is an important modifier.  
 
This is a well -performed study in an area of interest. However, there are some major comments 
related to this kind of study. We do not know the reason for initiation of the diagnostic process. 
Is it secondary to diabetes d iagnosis or IBD with increased likelihood of later admission to in -
patient care? Another problem is that children followed by a physician for CD are more likely to 
be evaluated and treated for other common diseases. As part of follow -up they are also more 
often blood sampled and evaluated for anemia, autoimmune thyroiditis and liver disease. This is 
mentioned (P10 R14) but this results in an overestimation of complications to celiac disease, 
which needs to be discussed.  
 
The statistics of the paper has been discussed with a statistician. Cox regression is an appropriate 
method on this type of material. One objective and also mentioned in the title is the role of 
maternal education. However, since the matching is done on ma ternal education the design of the 
study is not the best to study this. The comparisons made are the only possible with this design 
but as also mentioned in the discussion, the numbers are small and CI very wide making these 
comparisons weak.  
 
Minor commen ts 
 
P5 R2 Should say FVG region  
P5 R4 Should say "in Italy outside the region".  
P5 R6 Is also the prescription registry national?  
P6 R13 Explain why follow -up is started after 30 days.  
P7 R16 How was the distribution of basis for CD classification - (%) pa thology report, (%) 
hospital discharge and  (%) copayment? IBD was common in the material and villous atrophy is 
also related to Crohns disease.  
P7-9 HR and CI is a repeat from tables and could be excluded in the running text to make 
reading easier.  
P9 R8 Maternal education 50+12+12%. The rest?  
P11 R13 Is thrombocytopenia and leukopenia related to malabsorbtion?  
 
Other questions/comments:  
 
In what extent is information missing in the material. Maternal education and so on?  
How is the results effected by th e migration?  
It is difficult to understand why cardiovascular and neurological prescriptions are increased 
during first year and not later since these diseases are unlikely to disappear.  
It is a contradiction that hospitalization by infections and respirat ory disease is increased but 
prescription for the same is not.  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
No 
 
Are you able to assess any statistics in the manuscript or would y ou recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from 
an organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financi ally from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organiz ation that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of th e above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under  an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title: Risks of hospitalization and drug consumption in children and young adults with 
diagnosed  celiac disease and the role of maternal education: a population -based matched birth 
cohort study.  
 
 
Version: 0 Date: 25 Nov 2015  
 
 
Reviewer: Olof Sandstr öm 
 
 
Reviewer's report:  
 
"Risks of hospitalization and drug consumption in children and young adults with diagno sed 
celiac disease and the role of maternal education: a population -based matched birth cohort study" 
by Canova et al (BMGE -D-15-00217)  
 
This is a registry -based study conducted in the region of Friuli -Venezia Giulia in Italy. It starts 
with a birth regist ry with information on maternal education that is linked to a national hospital 
discharge registry and a prescription registry (national?). CD diagnosis is based on ICD9 
diagnosis from hospital discharge registry, pathology reports or copayment data. To ea ch CD 
case up to 5 controls was selected, matched on maternal education, and sex and age of the CD 
case. The objectives are to study the effect of CD on the use of health -care resources, the 
persistence of such a phenomena and if the maternal level of educ ations is an important modifier.  
 
This is a well -performed study in an area of interest. However, there are some major comments 
related to this kind of study. We do not know the reason for initiation of the diagnostic process. 
Is it secondary to diabetes d iagnosis or IBD with increased likelihood of later admission to in -
patient care? Another problem is that children followed by a physician for CD are more likely to 
be evaluated and treated for other common diseases. As part of follow -up they are also more 
often blood sampled and evaluated for anemia, autoimmune thyroiditis and liver disease. This is 
mentioned (P10 R14) but this results in an overestimation of complications to celiac disease, 
which needs to be discussed.  
 
The statistics of the paper has been discussed with a statistician. Cox regression is an appropriate 
method on this type of material. One objective and also mentioned in the title is the role of 
maternal education. However, since the matching is done on ma ternal education the design of the 
study is not the best to study this. The comparisons made are the only possible with this design 
but as also mentioned in the discussion, the numbers are small and CI very wide making these 
comparisons weak.  
 
Minor commen ts 
 
P5 R2 Should say FVG region  
P5 R4 Should say "in Italy outside the region".  
P5 R6 Is also the prescription registry national?  
P6 R13 Explain why follow -up is started after 30 days.  
P7 R16 How was the distribution of basis for CD classification - (%) pa thology report, (%) 
hospital discharge and  (%) copayment? IBD was common in the material and villous atrophy is 
also related to Crohns disease.  
P7-9 HR and CI is a repeat from tables and could be excluded in the running text to make 
reading easier.  
P9 R8 Maternal education 50+12+12%. The rest?  
P11 R13 Is thrombocytopenia and leukopenia related to malabsorbtion?  
 
Other questions/comments:  
 
In what extent is information missing in the material. Maternal education and so on?  
How is the results effected by th e migration?  
It is difficult to understand why cardiovascular and neurological prescriptions are increased 
during first year and not later since these diseases are unlikely to disappear.  
It is a contradiction that hospitalization by infections and respirat ory disease is increased but 
prescription for the same is not.  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
No 
 
Are you able to assess any statistics in the manuscript or would y ou recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from 
an organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financi ally from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organiz ation that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of th e above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under  an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title: Risks of hospitalization and drug consumption in children and young adults with 
diagnosed  celiac disease and the role of maternal education: a population -based matched birth 
cohort study.  
 
 
Version: 0 Date: 25 Nov 2015  
 
 
Reviewer: Olof Sandstr öm 
 
 
Reviewer's report:  
 
"Risks of hospitalization and drug consumption in children and young adults with diagno sed 
celiac disease and the role of maternal education: a population -based matched birth cohort study" 
by Canova et al (BMGE -D-15-00217)  
 
This is a registry -based study conducted in the region of Friuli -Venezia Giulia in Italy. It starts 
with a birth regist ry with information on maternal education that is linked to a national hospital 
discharge registry and a prescription registry (national?). CD diagnosis is based on ICD9 
diagnosis from hospital discharge registry, pathology reports or copayment data. To ea ch CD 
case up to 5 controls was selected, matched on maternal education, and sex and age of the CD 
case. The objectives are to study the effect of CD on the use of health -care resources, the 
persistence of such a phenomena and if the maternal level of educ ations is an important modifier.  
 
This is a well -performed study in an area of interest. However, there are some major comments 
related to this kind of study. We do not know the reason for initiation of the diagnostic process. 
Is it secondary to diabetes d iagnosis or IBD with increased likelihood of later admission to in -
patient care? Another problem is that children followed by a physician for CD are more likely to 
be evaluated and treated for other common diseases. As part of follow -up they are also more 
often blood sampled and evaluated for anemia, autoimmune thyroiditis and liver disease. This is 
mentioned (P10 R14) but this results in an overestimation of complications to celiac disease, 
which needs to be discussed.  
 
The statistics of the paper has been discussed with a statistician. Cox regression is an appropriate 
method on this type of material. One objective and also mentioned in the title is the role of 
maternal education. However, since the matching is done on ma ternal education the design of the 
study is not the best to study this. The comparisons made are the only possible with this design 
but as also mentioned in the discussion, the numbers are small and CI very wide making these 
comparisons weak.  
 
Minor commen ts 
 
P5 R2 Should say FVG region  
P5 R4 Should say "in Italy outside the region".  
P5 R6 Is also the prescription registry national?  
P6 R13 Explain why follow -up is started after 30 days.  
P7 R16 How was the distribution of basis for CD classification - (%) pa thology report, (%) 
hospital discharge and  (%) copayment? IBD was common in the material and villous atrophy is 
also related to Crohns disease.  
P7-9 HR and CI is a repeat from tables and could be excluded in the running text to make 
reading easier.  
P9 R8 Maternal education 50+12+12%. The rest?  
P11 R13 Is thrombocytopenia and leukopenia related to malabsorbtion?  
 
Other questions/comments:  
 
In what extent is information missing in the material. Maternal education and so on?  
How is the results effected by th e migration?  
It is difficult to understand why cardiovascular and neurological prescriptions are increased 
during first year and not later since these diseases are unlikely to disappear.  
It is a contradiction that hospitalization by infections and respirat ory disease is increased but 
prescription for the same is not.  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
No 
 
Are you able to assess any statistics in the manuscript or would y ou recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from 
an organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financi ally from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organiz ation that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of th e above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under  an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant