PONE-D-20-02036

Acanthosis Nigricans as a Composite Marker of Cardiometabolic Risk and Its Complex Association with Obesity and Insulin Resistance in Mexican American Children

PLOS ONE

Dear Dr. Juan Carlos Lopez-Alvarenga,

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PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: This manuscript describes the relationship between obesity, insulin resistance (IR), and acanthosis nigricans (AN). The relationship among these factors is not novel, but the authors have a novel statistical approach using many variables, genetics, and phenotypic. They found that obesity explains the association of IR with AN, but no causal relationship between IR and AN in Mexican American children. The results of this study could be important in clinical practice due to the AN severity-classification, which is low-cost, and it seems to be easy to measure, is correlated with cardiometabolic factors. However, the manuscript has critical methodological issues that need clarification and to be revised.

Main Concerns

1. The kinship of the sample is not describing in the manuscript; I mean the pairs of full or half-brothers, cousins, etc. It is not clear which kind of parentage was used for hereditability estimation; in other words, it is not clear which kinship measures fed the model. It is also not clear if hereditability is the only genetic variable used in the study.

2. Describe criteria cut-off for prediabetes and cardiometabolic factors; cut-of for dichotomized IFG, IGT, HDL-C, blood pressure and son on.

3. Which were the environmental variables used? Those need clarification.

4. The authors mention three methods to choose the best model (goodness-of-fit statistics, Akaike information criterion, and Bayes information). Still, they did not specify the threshold criterion to select the models. For example, mention the difference in the AIC values. This is a concerning matter for the reproducibility and the credibility of the chosen best model.

5. Mediation analysis has enough statistical power, but what about with the variance components analysis?

6. For clinical practice, are the pediatricians familiarized with the AN severity scale used in this study? If they are not, extending the AN as a proxy of cardiometabolic factors could be a limitation.

Reviewer #2: Please add a brief discussion on the ethnicity of the experimental group, in addition to describing them as Mexican Americans please provide more information on the ethnic ancestry of their two previous generations. It is also relevant to know if they were born in the US, if they are US citizens, or if they were born in Mexico and migrated to the US. This would provide a better understanding on the possible applications of the reported results to Mexican children living in urban areas similar to the state of Texas, such as the nearby city of Monterrey, Nuevo Leon, Mexico.

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Reviewer #1: No

Reviewer #2: Yes: Julio Granados

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Acanthosis Nigricans as a Composite Marker of Cardiometabolic Risk and Its Complex Association with Obesity and Insulin Resistance in Mexican American Children

PONE-D-20-02036R1

Dear Dr. Lopez-Alvarenga,

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,

Fernando Guerrero-Romero, MD, PhD

Academic Editor

PLOS ONE

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Reviewers' comments: