Reviewer’s report
Title: 
Can the dynamic spectral imaging (DSI) color map improve colposcopy
examination for precancerous cervical lesions? A prospective evaluation of the
DSI color map in a multi-biopsy clinical setting
Version: 
0 
Date: 
23 Oct 2020
Reviewer's report:
Authors describe the results from a prospective study carried out in a Regional
Hospital in Denmark evaluating the performance of Dysis compared to standard
colposcopy for the detection of CIN. An important advantage of the study is the
performance of four biopsies following colposcopic examination based on
national guidelines. Indeed, performing multiple biopsies does offer the
opportunity to better assess diagnostic accuracy. However, this is quite
uncommon, as discussed by the authors, when performing colposcopy in other
countries in Europe and the USA where biopsies are usually taken from the
abnormal areas only. For this reason, I would recommend that authors specify
which "real-life setting" they refer to as the title by itself could be misleading.
Overall results can add to the evidence available on the value of Dysis as an
adjunct to standard coloposcopy. However I have some concerns and
clarifications to be made:
1- Introduction and purpose:
I understand the main objective of the study is to assess the ability of Dysis to
discriminate between high and low grade lesions, and this purpose is achieved
by comparing the DSI map with the directed-biopsy from the worst area (given
by Dysis) and by comparing to the final histology (independently from the result
of the biopsy from the area suggested by the DSI map). 
It is essential to take into account the importance of training and experience and
the caveats associated to its subjective assessment. Do colposcopists in your
hospital receive specific training in colposcopy and the use of Dysis and
interpretation of the color map?
2- Methods:
Please include all exclusion criteria in same paragraph as it is otherwise
confusing to read.
Inclusion criteria included abnormal screening referrals (n=464) and cases
followed up for previous CIN diagnosis (n=68). Were all the latter under active
surveillance? Exclusion criteria include a biopsy within six months, does this
mean none of the cases included under the follow-up criteria under active
surveillance had a biopsy in the previous six month visit? 
Although cervical screening cytologies reported as invasive were considered as
inclusion criteria, there were no cases included in the study as illustrated in table
1. In the corresponding results section it would be interesting to highlight this
and relate to the cytology result. 
Low-grade was considered as ASCUS/LSIL cytology or previous follow-up for
CIN1. High-grade was considered when HSIL, ASC-H, AGC, invasive (although
there did not seem to be any cases) or follow-up for CIN2+ diagnosis. Authors
include "ungraded CIN" as CIN2+ because they are managed in the same way.
However, I believe this is misleading because it might be that some of these 11
cases might have actually been a CIN1 (irrespective of the follow-up) and would
therefore have fallen into the low-grade group. Where were the "unknown" cases
(n=3) classified? In addition, some of the CIN2+ cases might have regressed
during follow-up (authors do not specify the time since the diagnosis of CIN),
and might at the time of colposcopy have an ASCUS/LSIL, and would therefore
fall into the low-grade group. How can authors be sure of this? If it is not
possible to know, all these cases should be excluded from the analysis as they
may be misleading the results that authors described associated to the baseline
classification low-grade vs high-grade. 
Did both pathologists assess each of the biopsies or was it one pathologist or the
other depending on the case? Please clarify.
3 - Results:
One should note that 63.9% of cases the colposcopists and DYSISmap agreed on
the lesion to biopsy. This means that many of the conclusions do not only apply
to DSI map alone but also to standard colposcopy. This should be discussed. 
When comparing performance of DYSISmap for low-grade and high-grade
referrals do these include all patients or only the cervical screening cases?.
In the text authors only seem to emphasize the overall performance values,
although available in the tables I think it would be important to include the
differences observed in low-grade and high-grade referrals as these are more
comparable to previous results by other authors.
Authors should be cautious with the results obtained when comparing the DSI
map versus FHD of four biopsies (page 6). One must keep in mind that there is a
64% concordance with colposcopists impression of what was the worst lesion
(refer to previous comment). 
Given that Dysis in an adjunct to standard colposcopy, what are the performance
values when considering Dysis and standard colposcopy biopsies (ie those
colposcopists chose as worse when it did not coincide with DYSISmap)?
Additionally, authors claim that figure 3 shows lowest-grade colors on the
DYSISmap were evenly distributed, when actually the graphs are very similarly
distributed to those in figure 2. 
Could authors clarify the results form sentence in page 6 line 169. Of these 99
women, 38 had CIN3+, and 52.6% (20 of 38) had colors indicating low-grade
disease as the worst color on the DSI color map. Does it refer to the CIN3 cases?
In page 6 line 162: Histological diagnosis of DSI-directed biopsy compared to
FHD of four biopsies authors start the paragraph saying they calculated
sensitivity. This is misleading as it seems they did this alone for these particular
cases when they actually calculated all performance variables as illustrated later
in the text. 
4 - Discussion:
Please review statements on performance of Dysis at the start of the discussion
based on previous comments of which cases were included and what was
considered to be low-grade and high-grade cases in the methods section. 
Authors discuss the work by Lowers et al 2011, authors make vague statements
such as "The cytology referrals were also classified slightly differently". If you
believe this is relevant please expand. 
In page 7 lines 192-195 authors say that colposcopists may be over-reporting
acetowhightening when compared to DSI map, given that authors performed
four biopsies for whom separate histological results are available authors should
actually expand and give information on these results rather than making
hypothesis. 
Authors discuss the relation between acetowightening and HPV infection,
however they do not have information on the HPV genotypes, this should be
noted. They simply refer to the impact that vaccination may have on the DSI
map. However, this does not mean they were HPV 16 negative. Please clarify
what authors mean to discuss in this point. 
Page 8 line 221: remove as is expected. Statement should be based on the
evidence available not what authors expect. 
Page 9 lines 222-223: The sentence regarding conservative management of CIN2
is misleading because we can't know beforehand if a lesion will regress or not,
we can offer conservative management and observe how it behaves. 
Finally, could authors clarify why approval and registration of the study was
performed retrospectively after completion given that patients signed an
informed consent at entry?
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Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
Yes
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes