Title: Comorbidities in women with polycystic ovary syndrome: a sibling study
Version: 0 Date: 26 Oct 2023
Reviewer's report:
Comorbidities in women with polycystic ovary syndrome: a sibling study
This is an important study and the sibling design is extremely informative. The paper is very
ambitious but very thoughtful. However, I would prefer it to be reduced in complexity by cutting
it into two papers, at least – sorry.  It is very complex for the readership and the tables reflect
the overly complex sub-analyses by having partially blank columns.
Below are a number of specific comments.
Limitations: The non-PCOS group may be undiagnosed, as the diagnosed sib may simply being
the one seeking care first for, say, sub-fertility.  So, is the PCOS diagnosed sib older? The sibling
age and parity data are not obvious.
The study is limited to singletons.  Quite reasonably, but a limitation is that PCOS births more
likely to occur after ovulation induction as mother also likely to have PCOS and therefore
anovulatory infertility. Perhaps this is a matter for comment.
Now, line by line.  Please consider the references as others have been here before.
L75  Autonomic dysregulation may be a common upstream factor for hyperphagia and sex
hormone perturbation.  Ditto for sleep apnoea. Please see Nat Sci Sleep  2018 Feb 1:10:45-64.
doi: 10.2147/NSS.S127475. eCollection 2018.
L78  clustering of symptoms, such sleep disorders and depression. Please see Hum Reprod  2021
Jul 19;36(8):2275-2284. doi: 10.1093/humrep/deab101
L83  Indeed, the majority of women with PCOS do not have a diagnosis. Pls see above.
L97 This has already been demonstrated, but not with siblings. Please emphasise the novelty of
your design in response!  Hum Reprod. 2012 May;27(5):1475-80. doi: 10.1093/humrep/des027.
Epub 2012 Feb 28.
L145 The use of outpatient data and record linkage has limitations as it is uncalibrated and
diagnostic  criteria uncertain.  Similarly, confounding by indication is a major problem with
outpatient data. The patent presentation of difficulties to conceive readily results in PCOS
diagnosis, especially if obesity is present.  Those not yet presenting for sub-fertility may go
undiagnosed. Please mention in limitations section.
L196  This is a very ambitious paper and may struggle to answer all the questions well within
the word limits. Consider splitting into 2 or even 3.
L197  I don’t think the analysis need to be confined exclusively sibs discordant for an outcome.
Each individual can have a binary outcome for, say diagnosis of depression, and the question
becomes ‘is the PCOS sib more likely to have depression, yes or no”.
L218 Do you have birth order and parity?  I suspect the PCOS sib may be the older if diagnosis
follows presentation for infertility.  The first born may also be more likely to have a diagnosis
of PCOS as the first pregnancy is more likely to have relevant pregnancy complications such
as preeclampsia, prematurity, LBW.
L121 What bias is introduced by allowing loss to follow-up?
L223  This is the point at which this question is a separate paper, as this goes to testing biological
plausibility within a highly restricted sub-set, which is valid but tricky to include within a data
linkage study where a strength is representativeness and inclusivity.
Table 1 indicates the paper is too complex as it reports demographic and outcome data together,
plus sub-groups.  The empty cells for birth weight indicate that another table is needed.
I cant follow the data flows or the table legends. Where is the STROBE figure? Where is the
reference group for the analytic tables? I cant follow the derivation of the MBR sub-sample.
L257 The rationale for the interactions has not been described. I can propose them, but its due
to confounding. 1) This can go either way as obesity relates to social deprivation, however, high
SES correlates with medical interventions and a greater rate of diagnosis, so there may be an
interaction of SES for high BMI 2) ethnic variations in Ferriman-Gallwey scores vary greatly by
ethnicity.  So, the absence of interaction indicates this is a relatively homogenous study group
due to selection processes, as described.
L263  Again, the sampling frame is not obvious.
L321 it’s stated that  “..PCOS have 4-fold increased odds of being diagnosed with obesity…”.
However, I’d also suggest the obverse, obese women have a 4-fold increased odds of being
diagnosed with PCOS!  Obesity certainly provides an independent path to anovulatory infertility
which is a cardinal feature of PCOS. Obesity may also precede PCOS, and becomes a convenient
diagnostic device.
L350 PCOS is FAMIAL which is not necessarily HERITABLE.  There is no clear genetic
pathway as yet. This para is unclear.
L360-363 This is garbled. I cant follow the argument. Please rephrase.
L390 Access to, and willingness to seek, care for reproductive disorders will also alter the
relationship between presenting symptoms, diagnosis, and thereby the relationship between
variables. The precise extend of this bias is currently unknown, but is possibly substantial, as
the majority of women with PCOS do not have a diagnosis (see Marino ref above).
L393 Familial rather than familiar.