Reviewer ’s report  
 
Title: Mitochondrial DNA copy number in cervical exfoliated cells and risk of cervical cancer  
among HPV -positive women  
 
Version: 0 Date: 23 Nov 2019  
 
Reviewer: Paolo Giorgi Rossi  
 
Reviewer's report:  
 
Abstract  
Please present some measure of the interaction between type and mtCN, do not comment only 
the significance, since analyses of interaction are always underpowered.  
In the conclusion: with such a weak association, mtCN is not promising as biomarker for the 
moment. If you try to calculate the PPV or the sensitivity of this mtCN as biomarker accuracy 
will be very low. In cervical cancer we have other biomarkers with much stronger associations, 
but maybe it will be important  when combined with other bi omarkers. Nevertheless, the findings 
are interesting for the possible causal link underlying this association.  
 
Introduction  
Pag 3 Line 52: HPV PPV is much less than 50%!!!  
The introduction is very well -written and helpful. I am not sure if the numbers of cases and 
controls should be mentioned here or in the methods section.  
 
Methods  
Can you describe very briefly the inclusion criteria of the non -cancer cohort? Furthermore, how 
many women were excluded from the cohort because cytology positive? HPV+ cyto ne gative 
women have not been also assessed to be colposcopy negative, isn't it? I think this is reasonable, 
but should be reported and discussed in the limits.  
 
Results  
I suggest to present the percentages and then to say if differences are significant or n ot. Please 
report the exact p  value and not only it is below or over the threshold. Particularly in a study in 
which there are several comparisons, the sample size has not been pre -determined and when 
presenting data not on the main outcome, reporting sta tistical significance as a formal statistical 
test is not meaningful.  
The same for the interaction analysis the main information is that the trend is consistent, not the 
significance of the interaction test that is not powered at all.  
In general the paragr aph is concise and clear.  
Please add a graph showing the distribution of the values in the two groups, to make clear if the 
difference between means is due to a small shift in the overall group or if it is due to few outliers. 
Box plots or frequency histog rams could be explicative for this.  
 
 
 
Discussion  
Pag 9 line 23, I think is "to date"  
Pag 9, last line: prospective studies are needed  to understand the direction of the causal link, and 
when in the pathogenetic process the association become clear, not to  confirm the association, 
for this your study is strong enough. But  such comments are more appropriate at the end of 
discussion.  
Pag 11 first sentence: the sentence is too generic. Please see the comment above.  
Please comment some of the limitations: you cannot exclude that in controls there are some 
CIN2 or CIN3, regarding cancers, cytology is very sensitive; the cases and the controls do not 
come exactly form the same population (actually I do not know if this is a real limit as I do not 
know  how the no n cancer cohort has been recruited); can you exclude some effects of the 
treatments in women with cancer? When the cell sample has been taken? These are only 
examples of possible biases in case control studies, please try to convince the readers that you 
considered all the possible limits.  
 
Conclusions  
See the comment on abstract conclusions.  
 
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.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would you 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:  
 
Needs some language corrections before being published  
 
 
Declaration of competing interests  
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