-->PONE-D-25-65362-->-->Persistent Symptoms, Cognitive Impairment, and Clinical Predictors of Long COVID One Year After Omicron Infection: A Clinical Case–Control Study from the Faroe Islands-->-->PLOS One

Dear Dr. Helmsdal,

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: I Don't Know

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Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Overall, this manuscript addresses an important topic and provides useful information about persistent symptoms after Omicron infection. The study design is clear and includes a control group of individuals who were not previously infected, which strengthens the analysis. The authors used questionnaires, clinical examination, and laboratory tests, providing a comprehensive evaluation of participants.

The results are presented clearly and the statistical methods appear appropriate. The findings regarding fatigue, cognitive symptoms, and mental impairment are consistent with previous studies on long COVID and add additional data from a well-defined population.

However, a few points could be clarified. The sample size of the control group is relatively small, which may limit the statistical power of the comparisons. It would also be helpful if the authors further explain the selection process for participants included in the clinical follow-up to better understand potential selection bias. In addition, more discussion on the clinical relevance of the laboratory findings, particularly the differences in white blood cell counts, would strengthen the interpretation of the results.

The manuscript is well organized and contributes meaningful data to the understanding of long COVID after Omicron infection.

Reviewer #2: Overall, this is a well thought out and well-written paper investigating risk factors for long COVID after the Omicron wave in a relatively isolated population in the Faroe islands. This paper describes risk factors in a society with access to modern health care and a relatively high national income. Several factors were identified that were associated with long COVID in this analysis. However, the discussion section particularly on limitations of the study are glossed over even with more uncommon methodologies.

Language:

Generally written appropriately throughout. Several instances of "Covid-19" vs. "COVID-19" in other places -- would keep this consistent throughout.

Intro:

No issues

Findings/discussion:

Overall describes the detais of case: control selection adequately, as well as the utilization of the survey and clinical data.

- The utilization of essentially 3 cases: 1 control is methodologically uncommon in the literature (usually controls up to 4 per case are general practice as increasing power/ability to detect a difference). Aside from the practical limitations related to the low seronegative rate, this is not addressed in either the methods section or in the discussion where it warrants further comment. Furthermore, the controls as being a highly selected group was not explored as a limitation in the contextualization of the findings.

- As such, there is no comment or discussion on power calculation or sample size.

- The use of confounds with p<0.05 in a univariate model for their multivariate model is potentially problematic and exposes to potential biases without great explanation why this approach was used. Usually confounders are determined by the expertise available. This reviewer will fully acknowledge a lack of expertise in statistics, but I am familiar with recommendations from scientific societies regarding methodological approaches in this setting. This is essentially a step-wise approach to confounding.

- It does not appear the authors have considered multiple comparisons across the many different variables and hypothesis tests between symptoms, neuropsychiatric symptoms

- The authors spent a decent portion of the results and discussion on WBC count differences between LC and NI groups, particularly related to differencs between sex. Overall, the differences as outlined demonstrate statistical significance but all well within a normal leukocyte count overall, yes the medians are different, but still well within a normal WBC count and this is not addressed in the discussion --- some readers might be asking whether or not these even matters. Why were the differences in WBC and sex not explored as an interaction term?

- Similarly, the focus on basophil significance without an explanation of a hypothesis -- it seems odd to this reviewer that basophils would be more significant than eosinophils. Again, this is not addressed in the discussion -- to me for these findings are statistically significant but there might not be a broader significance since no hypothesis or future direction is discussed.

- Lines 294-298 -- check reference, it sounds like it's Iba et al, but the refence of 28 is aksura --- I suspect this should be 29.

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Reviewer #1: Yes:   Yuriy Bisyuk

Reviewer #2: No

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Persistent symptoms, cognitive impairment, and clinical predictors of long COVID one year after Omicron infection: A clinical case–control study from the Faroe Islands

PONE-D-25-65362R1

Dear Dr. Helmsdal,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Petros Isaakidis

Academic Editor

PLOS One

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