PONE-D-23-04133Family and Personal History of Cancer in the All of Us Research Program for Precision MedicinePLOS ONE

Dear Dr. Bruce,

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"L.K.B, K.K., and L.O.M are supported by a grant through the NIH Directors office (OT2OD026552). T.H.M.K is supported by a grant through the National Cancer Institute (P30CA093373)."

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"L.K.B, K.K., and L.O.M are supported by a grant through the NIH Directors office (OT2OD026552). T.H.M.K is supported by a grant through the National Cancer Institute (P30CA093373)."

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Additional Editor Comments:

This paper is well written and contributes to the understanding of cancer prevalence rates in US and associations of family and personal histories with these rates. It is based on analysis of All of Us data collection and compared with participants from the 2015 National Health Interview Survey (NHIS). It is a comprehensive intriguing analysis. The paper can be further improved as suggested by both reviewers. See their comments.

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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: Yes

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

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The manuscript describes important findings for rates of certain types of cancers such as breast, colorectal, lung, prostate etc. from AoU cohort and compares it with NHIS cohort from self-reported family history (FH) and personal history (PH) survey questionnaires. Overall, the paper is well written, but is rather long and can be described more concisely in Results. It’s not clear what the main findings are – “we found similar family cancer history (33%) rates, but higher personal cancer history, with rates of personal cancer of nearly double in AoU as compared to the NHIS (9.2% vs. 5.11%)”. If it’s the latter, it will help the reader if they could describe results more concretely and point to the relevant tables.

Other comments -

Page 11-

a. 314,994 individuals who completed ‘The Basics’ survey � this number is larger in Table 1 (383,808) if its AoU v4

b. Table 2, foot note lists denominator as 89,458 where as the text lists as 89,453 from AoU with FH

c. Similarly, for AoU with FH + PH lists 89,142 vs. 89,152 in the text

Table 6, Page 22 – need N besides percentages for specific cancer types – in other words need to know how many in each bin for calculating conditional probability. This is the table that shows double rates?

Interestingly, colorectal cancer conditional probability remains same (2.20%) between AoU and NHIS cohorts in Table 6, while Breast cancer is doubled for AoU (10.10% vs 5.40%). Why such discrepancy? It may be also good to discuss, if it’s an artifact of data collection/survey methods?

Reviewer #2: This interesting manuscript compares rates of personal cancer history and family cancer history in the All of Us database and in NHIS. The paper is well written and technically describes surveys on large enough datasets (383,808 in All of Us, and 76,261 in NHIS), as well as in sub-cohorts of these datasets. The authors performed several summary statistics of the data, which can be seen in the tables in the main text and supplemental material. The code and datasets are open and available for any researcher who registers and completes the ethics training of All of Us.

Specific points to be addressed:

1.Materials and methods, Page 10: “with the hypothesis that prevalence statistics and trends would be comparable despite the differences in population composition”. If the study is hypothesis-driven, it would be ideal to state the hypothesis in the introduction. Materials and methods should state only well-described methods that can effectively answer the questions you are addressing.

2.Race and ethnicity categories were collected in the All of Us Research Program. Is it possible to also include the source of the classifications used (eg, self-report or selection, investigator observed, database, electronic health record, survey)?

3.Section “All of Us Study Cohort”: For those who are not familiar with the AoU database, what exactly does “the Basics” survey include? Which information does it contain? Please describe in one sentence or two.

4.Page 12, section “All of Us Dataset Preparation”, 1st sentence: word input was repeated twice.

5.Statistical Analysis, page 13: When stating the statistical methods used to analyze the data (two-sample proportion z-test), also state the p-value used for significance (was it .05? Then add “A p-value less than .05 was considered to indicate statistical significance.”

6.When mentioning statistical softwares/packages you used, also state version and manufacturer's name. Eg: We used numpy (version X.X.X, https://numpy.org) and pandas (version X.X.X., https://pandas.pydata.org). Same for jupyter notebook, and other libraries you used. This allows others to reproduce the study.

7.Table 1: Spell out the abbreviation “FH” in the table legend. The abbreviations E1, E2, E3 were defined but they do not appear in the table.

8.Maybe there is a typo in the first paragraph of Results: “the same level of diversity in seen”. Did you mean "as seen"?

9.Provide statistical significance (p-values) when comparing variables (race/ethnicity, age, biological sex) between cohorts. This is important to verify that your statistical analyses are performed to a high technical standard and are described in sufficient detail.

10.Under Results: “The demographic composition for the NHIS survey population and the FH subset are comparable for education and income while race and ethnicity are slightly skewed White, Female, and older.” Please rephrase this sentence. Perhaps “ […] while race/ethnicity and biological sex are slightly skewed towards White and female, respectively”

11.Discussion: “Like in previous studies, we found that the prevalence of FH and PH of cancer varies by age, race/ethnicity, income and education, and sex.” – can you cite which studies found these main observations?

12.This sentence is also missing a citation: “In CRC, previous studies have found that a higher proportion of patients with CRC diagnosed at 50 years of age or younger have a family history of the disease when compared to individuals diagnosed after this age.”

13.What were the limitations of your study? Was it the selection biases of AoU or NHIS recruitment that perhaps makes these two populations not comparable? Please state clearly in the discussion the limitations and biases inherent in your study.

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Reviewer #1: No

Reviewer #2: Yes: Vesna Barros

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Family and Personal History of Cancer in the All of Us Research Program for Precision Medicine

PONE-D-23-04133R1

Dear Dr. Bruce,

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,

Michal Rosen-Zvi

Academic Editor

PLOS ONE