A single measurement of fecal hemoglobin concentration outperforms polygenic risk score in colorectal cancer risk assessment
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Peer review report
Title: A single measurement of fecal hemoglobin concentration outperforms polygenic risk score in colorectal cancer risk assessment
version: 1
Referee: Andrea Buron
Institution: Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
email: aburon@psmar.cat
ORCID iD: E-5705-2016
General assessment
This is a well-written paper describing the compared utility of FIT and PRS as risk assessment tools, and as means of colorectal cancer screening. The results are very informative given that many screening programmes are currently using FIT and the evidence of using PRS as additional or alternative test in this context is scarce.
One of the main strengths of this study is its population, a cohort of participants in screening colonoscopy program which means that for all participants we have the colonoscopy …
Peer review report
Title: A single measurement of fecal hemoglobin concentration outperforms polygenic risk score in colorectal cancer risk assessment
version: 1
Referee: Andrea Buron
Institution: Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
email: aburon@psmar.cat
ORCID iD: E-5705-2016
General assessment
This is a well-written paper describing the compared utility of FIT and PRS as risk assessment tools, and as means of colorectal cancer screening. The results are very informative given that many screening programmes are currently using FIT and the evidence of using PRS as additional or alternative test in this context is scarce.
One of the main strengths of this study is its population, a cohort of participants in screening colonoscopy program which means that for all participants we have the colonoscopy result as well as the PRS and FIT result.
Essential revisions that are required to verify the manuscript
Some issues need some consideration:
The context and the study population is not sufficiently described: how does the German screening colonoscopy program work (exclusion and inclusion criteria, invitation methods, funding and cost to the participant), also main results especially in terms of uptake rates and how any differences by age, sex, etc.
Include at least in the discussion possible issues that might affect representability of the study population compared to the general population, and whether this might potentially alter the study results. Ideally, a (annex o supplementary) table describing the characteristics of non-participants in the program as well as non-participants in the study would be very informative in this regard.
Other suggestions to improve the manuscript
- Authors say that “FIT-based risk assessment is restricted to CRC risk” – there is evidence that FIT tests are useful to predict not only CRC but also pre-neoplasic disease. Also, to a less extent, it has been found to correlate and act as a potential risk marker of other non-digestive diseases.
- As part of the discussion, authors do not comment on the possibility of using FIT and PRS concomitantly. It would be very interesting to know if their results they could further inform in this direction, on whether adding a PRS test to FIT could improve the prediction and hence better select the population in which to recommend colonoscopy.
Decision
Verified with reservations: The content is scientifically sound but has shortcomings that could be improved by further studies and/or minor revisions.
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Peer review report
Title: A single measurement of fecal hemoglobin concentration outperforms polygenic risk score in colorectal cancer risk assessment
version: 1
Referee: Iris Lansdorp-Vogelaar
Institution: Erasmus MC, Rotterdam, the Netherlands
email: i.vogelaar@erasmusmc.nl
ORCID iD: 0000-0002-9438-2753
General assessment
This is a well conducted study, clearly written study. The main strengths of the study include the novelty of the topic, its large sample size and that physicians and lab analysts were blinded to each other’s outcomes. There are few weaknesses. First, FIT and SNPs in essence service different purposes. Although I agree with the authors that FIT can be used both ways, this deserves more explicit explanation in the discussion section. Second, I disagree with the exclusion of non-advanced adenomas as relevant findings. …
Peer review report
Title: A single measurement of fecal hemoglobin concentration outperforms polygenic risk score in colorectal cancer risk assessment
version: 1
Referee: Iris Lansdorp-Vogelaar
Institution: Erasmus MC, Rotterdam, the Netherlands
email: i.vogelaar@erasmusmc.nl
ORCID iD: 0000-0002-9438-2753
General assessment
This is a well conducted study, clearly written study. The main strengths of the study include the novelty of the topic, its large sample size and that physicians and lab analysts were blinded to each other’s outcomes. There are few weaknesses. First, FIT and SNPs in essence service different purposes. Although I agree with the authors that FIT can be used both ways, this deserves more explicit explanation in the discussion section. Second, I disagree with the exclusion of non-advanced adenomas as relevant findings. Given that the authors suggest using FIT/SNPs for risk prediction at younger ages, non-advanced adenomas are also relevant because with time they could develop into colorectal cancer.
Essential revisions that are required to verify the manuscript
There is an essential difference between SNPs and FIT: SNPs predict risk of developing colorectal lesions, whereas FIT signals presence of colorectal lesions. In the current manuscript, SNPs are essentially compared on their performance to detect advanced neoplasms, which is not their intention. Yet, I agree with the authors that in order to predict development of colorectal cancer, one would expect the presence of precursor lesions >10 years prior and thus the performance can be compared that way. However, this is not immediately obvious. I therefore feel very strongly that this difference in initial purpose should be more explicitly explained in the discussion section, and also the argument why this comparison is reasonable nevertheless.
Given the above point, I feel that non-advanced adenomas should be included as relevant findings. The purpose of SNPs/FIT in this paper is to predict colorectal cancer risk for stratified screening approaches. In that case, non-advanced adenomas are relevant for future cancer risk in 10+ years. Omitting these basically makes the tests focused on early detection rather than risk prediction and stratification.
Other suggestions to improve the manuscript
Genotyping was done on a random age- and sex- matched sample of participants without advanced neoplasms before applying exclusion criteria. As a consequence, there actually was an age- and sex-difference between participants with and without advanced neoplasms in the study. Would it not have been better to age- and sex- match after exclusion criteria were applied.
Provide statistical tests for difference in baseline characteristics between participants with and without advanced neoplasms in Table 1.
- Have the authors evaluated a combined approach of FIT and SNPs to see if that improves risk prediction and outperforms use of either one separately.
Decision
Requires revisions: The manuscript contains objective errors or fundamental flaws that must be addressed and/or major revisions are suggested.
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