Title: Evaluation of the causal effects of blood metabolites on irritable bowel syndrome:
Mendelian randomization
Version: 0 Date: 01 Nov 2023
Reviewer's report:
This paper is a solid contribution with novel results. However, there are some details that require
attention.
A general concern is that multiple testing is not addressed. 486  metabolites are tested but I don't
see any correction for that.
73 The phrasing “MR studies utilize genetic variations resulting from long-term exposure as …”
suggests that the genetic variation might be somatic mutations, and so it should be rephrased.
114 The narrative distinction between the two samples should be made more distinct (even just
a paragraph break would do). There is also a relative paucity of information on the IBS sample
relative to the description of the metabolites sample. Finally, the degree to which the sample
populations are comparable should be addressed.
121 “we eased the selection parameters and established a significance threshold …” is (I think)
just “we relaxed the significance threshold to …”. That is, no other criteria were changed.
125 There should be some explanation of why the criteria listed here are different than in the
preceding sentences.
127 The cited paper (16) specifically recommends against simply using a threshold of F of 10
to avoid weak instruments.
149 Post-hoc power analysis is almost always ill-advised, and I don’t believe ref (23) is intended
for post-hoc power as used here.
162 I don’t understand why the FinnGen data is used as part of meta analysis instead of
replication. Could the authors address this? The Finnish population is somewhat distinct from
other parts of Europe---the authors might address whether that matters in the present context.
168 “Genetic correlation is a common method of genetic correlation analysis …” has to be
rewritten.
171 I don’t think (25) is the intended reference.
I’m afraid I don’t understand the use of the term genetic correlation for association of a snp and
phenotype. Isn’t genetic correlation used in the context of two or more distinct phenotypes? Do
the authors mean snp-specific heritability? For example, table 2 is labeled as showing heritability
while genetic correlation is named.
214 A reference is missing.
248 Four subtypes are mentioned by only three are specified. Since these subtypes are not used
in the analysis, they could be omitted or the connection to the present study  made more explicit.
266 Given that four metabolites have been found to be associated, why write that two of them
“appear to be the risk factors for IBS”? Writing “the” is also rather assertive, rather than writing
“appear to be risk factors for IBS.”
Fig 1 has several typos.
Title: Evaluation of the causal effects of blood metabolites on irritable bowel syndrome:
Mendelian randomization
Version: 0 Date: 01 Nov 2023
Reviewer's report:
This paper is a solid contribution with novel results. However, there are some details that require
attention.
A general concern is that multiple testing is not addressed. 486  metabolites are tested but I don't
see any correction for that.
73 The phrasing “MR studies utilize genetic variations resulting from long-term exposure as …”
suggests that the genetic variation might be somatic mutations, and so it should be rephrased.
114 The narrative distinction between the two samples should be made more distinct (even just
a paragraph break would do). There is also a relative paucity of information on the IBS sample
relative to the description of the metabolites sample. Finally, the degree to which the sample
populations are comparable should be addressed.
121 “we eased the selection parameters and established a significance threshold …” is (I think)
just “we relaxed the significance threshold to …”. That is, no other criteria were changed.
125 There should be some explanation of why the criteria listed here are different than in the
preceding sentences.
127 The cited paper (16) specifically recommends against simply using a threshold of F of 10
to avoid weak instruments.
149 Post-hoc power analysis is almost always ill-advised, and I don’t believe ref (23) is intended
for post-hoc power as used here.
162 I don’t understand why the FinnGen data is used as part of meta analysis instead of
replication. Could the authors address this? The Finnish population is somewhat distinct from
other parts of Europe---the authors might address whether that matters in the present context.
168 “Genetic correlation is a common method of genetic correlation analysis …” has to be
rewritten.
171 I don’t think (25) is the intended reference.
I’m afraid I don’t understand the use of the term genetic correlation for association of a snp and
phenotype. Isn’t genetic correlation used in the context of two or more distinct phenotypes? Do
the authors mean snp-specific heritability? For example, table 2 is labeled as showing heritability
while genetic correlation is named.
214 A reference is missing.
248 Four subtypes are mentioned by only three are specified. Since these subtypes are not used
in the analysis, they could be omitted or the connection to the present study  made more explicit.
266 Given that four metabolites have been found to be associated, why write that two of them
“appear to be the risk factors for IBS”? Writing “the” is also rather assertive, rather than writing
“appear to be risk factors for IBS.”
Fig 1 has several typos.
Please review this paper.
user
Title: Evaluation of the causal effects of blood metabolites on irritable bowel syndrome:
Mendelian randomization
Version: 0 Date: 01 Nov 2023
Reviewer's report:
This paper is a solid contribution with novel results. However, there are some details that require
attention.
A general concern is that multiple testing is not addressed. 486  metabolites are tested but I don't
see any correction for that.
73 The phrasing “MR studies utilize genetic variations resulting from long-term exposure as …”
suggests that the genetic variation might be somatic mutations, and so it should be rephrased.
114 The narrative distinction between the two samples should be made more distinct (even just
a paragraph break would do). There is also a relative paucity of information on the IBS sample
relative to the description of the metabolites sample. Finally, the degree to which the sample
populations are comparable should be addressed.
121 “we eased the selection parameters and established a significance threshold …” is (I think)
just “we relaxed the significance threshold to …”. That is, no other criteria were changed.
125 There should be some explanation of why the criteria listed here are different than in the
preceding sentences.
127 The cited paper (16) specifically recommends against simply using a threshold of F of 10
to avoid weak instruments.
149 Post-hoc power analysis is almost always ill-advised, and I don’t believe ref (23) is intended
for post-hoc power as used here.
162 I don’t understand why the FinnGen data is used as part of meta analysis instead of
replication. Could the authors address this? The Finnish population is somewhat distinct from
other parts of Europe---the authors might address whether that matters in the present context.
168 “Genetic correlation is a common method of genetic correlation analysis …” has to be
rewritten.
171 I don’t think (25) is the intended reference.
I’m afraid I don’t understand the use of the term genetic correlation for association of a snp and
phenotype. Isn’t genetic correlation used in the context of two or more distinct phenotypes? Do
the authors mean snp-specific heritability? For example, table 2 is labeled as showing heritability
while genetic correlation is named.
214 A reference is missing.
248 Four subtypes are mentioned by only three are specified. Since these subtypes are not used
in the analysis, they could be omitted or the connection to the present study  made more explicit.
266 Given that four metabolites have been found to be associated, why write that two of them
“appear to be the risk factors for IBS”? Writing “the” is also rather assertive, rather than writing
“appear to be risk factors for IBS.”
Fig 1 has several typos.
assistant