Reviewer ’s rep ort 
 
Title: The use of electronic healthcare records for colorectal canc er screening referral decisions 
and risk prediction model development  
 
Version: 1 Date: 26 Nov 2019  
 
Reviewer: Tim Eglinton  
 
Reviewer's report:  
 
The authors present an ambitious project to attempt to improve the accuracy of CRC screening 
using a large primary care database containing multiple other relevant clinical features.  
 
A large dataset was amassed from the THIN database. 28 clinical features were analysed.  
Completeness of variables and univariable associations were assessed. Risk prediction models 
were developed using Cox regression and multivariable fractional polynomia ls with backwards 
elimination. Patients with a subsequent diagnosis of CRC or any polyp within two years were 
identified. Two models considered were any FOBT result and then only those with a negative 
FOBT result.  
 
In the FOBT positive and negative group t he presence of a positive FOBT was the strongest 
predictor. The addition of other factors did appear to improve the accuracy but it is not clear that 
this would help in  a clinical context as all positive FOBT patients would still need to be 
screened.  
 
Likewise in the FOBT negative group, while the combination of other clinical factors did 
generate a modest increase in risk for CRC/polyps, the authors admit that the specificity was too 
low for use as a screening tool.  
 
The data is limited by incomplete reco rds and also biased by ascertainment although the authors 
acknowledge this. The other limitation is the study uses guaiac FOBT that is now obsolete.  
 
The endpoint of CRC/polyps also detracts from the relevance. While this generates a higher 
number of outco me per degree of freedom for the multivariable models, it reduces clinical 
relevance. Would it be possible to analyse the dataset using only the outcome of CRC/Advanced 
adenoma to improve the clinical relevance. This is salient given emerging data suggesti ng low 
numbers of low risk adenomas have little influence on risk of carcinoma as reflected in the most 
recent BSG surveillance guidelines. In addition non neoplastic polyps would also be excluded.  
 
Given these criticisms, the final conclusion could be tem pered to reflect the comments made 
earlier in the discussion that the combination of clinical features analysed were not found to be 
clinically useful at present.  
 
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 con trols 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 you recomm end an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy 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 financial ly from the 
publication of this manuscript, either now or in the future?  
 
2.  Do you hold any stocks or shares in an organisation t hat 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 f or 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 in cluded as confidentia l comments 
to the editors, which will not be pu blished.  
 
I agree to the open peer review policy of the journal  
Reviewer ’s rep ort 
 
Title: The use of electronic healthcare records for colorectal canc er screening referral decisions 
and risk prediction model development  
 
Version: 1 Date: 26 Nov 2019  
 
Reviewer: Tim Eglinton  
 
Reviewer's report:  
 
The authors present an ambitious project to attempt to improve the accuracy of CRC screening 
using a large primary care database containing multiple other relevant clinical features.  
 
A large dataset was amassed from the THIN database. 28 clinical features were analysed.  
Completeness of variables and univariable associations were assessed. Risk prediction models 
were developed using Cox regression and multivariable fractional polynomia ls with backwards 
elimination. Patients with a subsequent diagnosis of CRC or any polyp within two years were 
identified. Two models considered were any FOBT result and then only those with a negative 
FOBT result.  
 
In the FOBT positive and negative group t he presence of a positive FOBT was the strongest 
predictor. The addition of other factors did appear to improve the accuracy but it is not clear that 
this would help in  a clinical context as all positive FOBT patients would still need to be 
screened.  
 
Likewise in the FOBT negative group, while the combination of other clinical factors did 
generate a modest increase in risk for CRC/polyps, the authors admit that the specificity was too 
low for use as a screening tool.  
 
The data is limited by incomplete reco rds and also biased by ascertainment although the authors 
acknowledge this. The other limitation is the study uses guaiac FOBT that is now obsolete.  
 
The endpoint of CRC/polyps also detracts from the relevance. While this generates a higher 
number of outco me per degree of freedom for the multivariable models, it reduces clinical 
relevance. Would it be possible to analyse the dataset using only the outcome of CRC/Advanced 
adenoma to improve the clinical relevance. This is salient given emerging data suggesti ng low 
numbers of low risk adenomas have little influence on risk of carcinoma as reflected in the most 
recent BSG surveillance guidelines. In addition non neoplastic polyps would also be excluded.  
 
Given these criticisms, the final conclusion could be tem pered to reflect the comments made 
earlier in the discussion that the combination of clinical features analysed were not found to be 
clinically useful at present.  
 
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 con trols 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 you recomm end an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy 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 financial ly from the 
publication of this manuscript, either now or in the future?  
 
2.  Do you hold any stocks or shares in an organisation t hat 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 f or 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 in cluded as confidentia l comments 
to the editors, which will not be pu blished.  
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s rep ort 
 
Title: The use of electronic healthcare records for colorectal canc er screening referral decisions 
and risk prediction model development  
 
Version: 1 Date: 26 Nov 2019  
 
Reviewer: Tim Eglinton  
 
Reviewer's report:  
 
The authors present an ambitious project to attempt to improve the accuracy of CRC screening 
using a large primary care database containing multiple other relevant clinical features.  
 
A large dataset was amassed from the THIN database. 28 clinical features were analysed.  
Completeness of variables and univariable associations were assessed. Risk prediction models 
were developed using Cox regression and multivariable fractional polynomia ls with backwards 
elimination. Patients with a subsequent diagnosis of CRC or any polyp within two years were 
identified. Two models considered were any FOBT result and then only those with a negative 
FOBT result.  
 
In the FOBT positive and negative group t he presence of a positive FOBT was the strongest 
predictor. The addition of other factors did appear to improve the accuracy but it is not clear that 
this would help in  a clinical context as all positive FOBT patients would still need to be 
screened.  
 
Likewise in the FOBT negative group, while the combination of other clinical factors did 
generate a modest increase in risk for CRC/polyps, the authors admit that the specificity was too 
low for use as a screening tool.  
 
The data is limited by incomplete reco rds and also biased by ascertainment although the authors 
acknowledge this. The other limitation is the study uses guaiac FOBT that is now obsolete.  
 
The endpoint of CRC/polyps also detracts from the relevance. While this generates a higher 
number of outco me per degree of freedom for the multivariable models, it reduces clinical 
relevance. Would it be possible to analyse the dataset using only the outcome of CRC/Advanced 
adenoma to improve the clinical relevance. This is salient given emerging data suggesti ng low 
numbers of low risk adenomas have little influence on risk of carcinoma as reflected in the most 
recent BSG surveillance guidelines. In addition non neoplastic polyps would also be excluded.  
 
Given these criticisms, the final conclusion could be tem pered to reflect the comments made 
earlier in the discussion that the combination of clinical features analysed were not found to be 
clinically useful at present.  
 
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 con trols 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 you recomm end an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy 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 financial ly from the 
publication of this manuscript, either now or in the future?  
 
2.  Do you hold any stocks or shares in an organisation t hat 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 f or 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 in cluded as confidentia l comments 
to the editors, which will not be pu blished.  
 
I agree to the open peer review policy of the journal  
assistant