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PONE-D-22-20954

The Association between Vitamin D Serum Levels, Supplementation, and Suicide Attempts or Intentional Self Harm

PLOS ONE

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    "This study was supported, in part, with resources from the Department of Veterans Affairs Center of Excellence for Suicide Prevention in support of the 2020 call by the Department of Veterans Affairs for research to support the national response to the COVID-19 pandemic.  This study does not represent the views of the Department of Veterans Affairs or the United States Government "

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 "This study was supported, in part, with resources from the Department of Veterans Affairs Center of Excellence for Suicide Prevention in support of the 2020 call by the Department of Veterans Affairs for research to support the national response to the COVID-19 pandemic.  This study does not represent the views of the Department of Veterans Affairs or the United States Government.  "

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Additional Editor Comments:

The authors should address the questions and comments of both reviewers.

Please address the questions and comments of both reviewers:  Reviewer 1. " I was very glad to see the review of these studies in this paper revealing their inadequacies and emphasizing that suicidal ideation and behavior were not assessed. But I wonder if that review might be more appropriate in the introduction rather than the discussion.

This study looks at suicide attempts and intentional self-harm resulting in emergency room or in-patient admission, which are much more definite and specific than depression and have some different brain mechanisms. It is a retrospective study using Veterans Affairs and Medicare electronic data, from 2010 to 2018, with patients prescribed Vitamin D matched 1:1 to untreated controls. It uses a very large sample: over half a million treated, nearly two million not treated controls: or is it three and a half million not treated? (D2 Controls plus D3 Controls.) Why are the numbers of Pre-matching D3 controls not the same as Pre-matching D2 controls? If they are a different pool of controls how were the controls chosen for each pool? Some further explanation might be useful. And related: why are there only 9,534 D3 controls with 0-19 Vitamin D level when there are 53,881 D2 controls with that level?

The treated patients were included from the date of their prescription. Were the untreated matched by that starting date?

It is fortuitous (and surprising to me) that so many had Vitamin D blood levels, especially as many with low levels were not treated (see below)

The dose used is mentioned and analyzed using the natural logarithm of average dosage (why?). I think mention of the range of dose used would be useful – especially as there is discussion of the appropriate dose under Practical and Policy Implications – but not based on the results of this study.

I don’t understand Propensity Score matching despite reading several descriptions on line. I will accept that it is legitimate. Someone experienced with it should decide its appropriateness. Is everyone expected to know what it means? If not, some more explanation might help. For example, if I look at Depression can I presume that for each Treated person there is a Control of the same gender, race, age (how close?) and any other characteristic?

Typo Table 1, Post-Matching Restricted Sample Control column, Age ?61 not 6.

Table 1 does confirm that people with Bipolar, Depression and other psychiatric conditions were more likely to be given Vitamin D although a greater number with these conditions were not treated, but the matching brought the numbers and the treatment likelihood to the same. The same is true for Vitamin D deficiency. All good.

Table 2, typo: Suicide Attempt by Control column, 0-19 Vitamin D Level Cohort line, should be 86, not 6. And some of the numbers don’t add up; for example, Vitamin D2 females: if there are 45,277 total females the treated should be about 22,742 not 227,420. It does look as if, when Vitamin D levels were very low, D3 was used preferentially for treatment but still about 63,000 with levels 0-19 were untreated. That raises the question of why blood levels were taken.

The Vitamin D2 Level Cohorts Suicide Attempts are surprising (not much difference) given the big differences in race and gender cohorts. That makes it hard to understand the last sentence of the Results section: “However, models of the serum level subsamples demonstrated notably lower rates with increasing blood serum levels relative to the full sample.” Is that for D2 as well as D3 or just the latter? And is there a higher rate of suicide attempts with Vitamin D when the blood level was over 40. (Yes, the numbers are too small. Still it reminds me of the association between maternal (or cord) blood levels and schizophrenia in the offspring – a J-shaped curve.)

Presumably the mental health comorbidities were taken from any time during the two years of treatment (or control). It is interesting to me that the beneficial effects of treatment continue with little change for the two years (Figures 1 and 2) when blood levels of Vitamin D normalize with treatment in two to three months.

Under Discussion, second paragraph, line 4, typo: did should be died. In the sixth line the word “by” presumably should not be there. I think it would be useful to say exactly what is meant by “precision medicine” – presumably only treating those with low Vitamin D levels."

Reviewer 2.  "Methods:  It seems from Table 1 that the pre- and post-matched control groups for Vitamin D2 and D3 were independent of each other (as the starting numbers are different). Statistically speaking, this is a benefit and should be noted in the methods.

Line 86. The authors should specify the vitamin D assays employed for blood measures (e.g. 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D or both etc.)

Lines 132-135. For the vitamin D blood serum subgroups, the variable ln{average daily dosage)} is very confusing, as the natural log of 0 is undefined (those with no daily Vit D (thus ln{0}). In lines 99-102, the authors describe weighting the average dose by the numbers of days supplies during the observation period, but this would still not seem to amend an undefined value for those with no vitamin D (the control groups). In which case, how were the controls employed in the subgroup analysis? A better description of this variable and how it was employed in the models would be very helpful.

Results:

Did the authors consider the condition of TBI as a potential covariate, give that in this veteran population TBI may be frequent, may differ between exposure groups, and could impact the outcomes of interest?

Do the authors have access to vitamin D blood levels after the onset of supplementation? As if so, analysis by those that reached sufficient levels, versus those with continued insufficiency and/or deficiency may be interesting.

Discussion:

Sentence starting “ A secondary analysis of these data by suggested…….” A word is missing here.

Final paragraph: Reference should be included in this paragraph starting from the sentence “Other trials included subjects with…..”.

Conclusion: Second line of paragraph- it would be better for the authors refer to the veterans by another definition, rather than “Patients”.

Table 1: There are some mistakes in the tables: (e.g. Table 1 age of the D3 post-matched controls; Table 2, 0-19 D2 cohort numbers of control N and treated N, do no sum to the total patient N). Checking of the tables is advised."

[Note: HTML markup is below. Please do not edit.]

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

**********

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

Reviewer #1: I Don't Know

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

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: I found this study very interesting and very revealing. I was very enthusiastic about Vitamin D 10-15 years ago and did a small study in people with schizophrenia but became disenchanted with it after a succession of negative studies were published, mainly in depression. I was very glad to see the review of these studies in this paper revealing their inadequacies and emphasizing that suicidal ideation and behavior were not assessed. But I wonder if that review might be more appropriate in the introduction rather than the discussion.

This study looks at suicide attempts and intentional self-harm resulting in emergency room or in-patient admission, which are much more definite and specific than depression and have some different brain mechanisms. It is a retrospective study using Veterans Affairs and Medicare electronic data, from 2010 to 2018, with patients prescribed Vitamin D matched 1:1 to untreated controls. It uses a very large sample: over half a million treated, nearly two million not treated controls: or is it three and a half million not treated? (D2 Controls plus D3 Controls.) Why are the numbers of Pre-matching D3 controls not the same as Pre-matching D2 controls? If they are a different pool of controls how were the controls chosen for each pool? Some further explanation might be useful. And related: why are there only 9,534 D3 controls with 0-19 Vitamin D level when there are 53,881 D2 controls with that level?

The treated patients were included from the date of their prescription. Were the untreated matched by that starting date?

It is fortuitous (and surprising to me) that so many had Vitamin D blood levels, especially as many with low levels were not treated (see below)

The dose used is mentioned and analyzed using the natural logarithm of average dosage (why?). I think mention of the range of dose used would be useful – especially as there is discussion of the appropriate dose under Practical and Policy Implications – but not based on the results of this study.

I don’t understand Propensity Score matching despite reading several descriptions on line. I will accept that it is legitimate. Someone experienced with it should decide its appropriateness. Is everyone expected to know what it means? If not, some more explanation might help. For example, if I look at Depression can I presume that for each Treated person there is a Control of the same gender, race, age (how close?) and any other characteristic?

Typo Table 1, Post-Matching Restricted Sample Control column, Age ?61 not 6.

Table 1 does confirm that people with Bipolar, Depression and other psychiatric conditions were more likely to be given Vitamin D although a greater number with these conditions were not treated, but the matching brought the numbers and the treatment likelihood to the same. The same is true for Vitamin D deficiency. All good.

Table 2, typo: Suicide Attempt by Control column, 0-19 Vitamin D Level Cohort line, should be 86, not 6. And some of the numbers don’t add up; for example, Vitamin D2 females: if there are 45,277 total females the treated should be about 22,742 not 227,420. It does look as if, when Vitamin D levels were very low, D3 was used preferentially for treatment but still about 63,000 with levels 0-19 were untreated. That raises the question of why blood levels were taken.

The Vitamin D2 Level Cohorts Suicide Attempts are surprising (not much difference) given the big differences in race and gender cohorts. That makes it hard to understand the last sentence of the Results section: “However, models of the serum level subsamples demonstrated notably lower rates with increasing blood serum levels relative to the full sample.” Is that for D2 as well as D3 or just the latter? And is there a higher rate of suicide attempts with Vitamin D when the blood level was over 40. (Yes, the numbers are too small. Still it reminds me of the association between maternal (or cord) blood levels and schizophrenia in the offspring – a J-shaped curve.)

Presumably the mental health comorbidities were taken from any time during the two years of treatment (or control). It is interesting to me that the beneficial effects of treatment continue with little change for the two years (Figures 1 and 2) when blood levels of Vitamin D normalize with treatment in two to three months.

Under Discussion, second paragraph, line 4, typo: did should be died. In the sixth line the word “by” presumably should not be there. I think it would be useful to say exactly what is meant by “precision medicine” – presumably only treating those with low Vitamin D levels.

Overall, I think it is a very good study, good methodology, with important findings.

Reviewer #2: In this interesting study, Lavigne & Gibbons set out to examine the benefits of exposure to Vitamin D, on the outcome of suicide. They performed a retrospective cohort study, using the extensive VA database of medical and pharmacy records, covering a period of approximately 8 years. Cox proportional hazards models were employed to estimate the association between vitamin D exposure (D2 or D3), on suicide attempt or death, with stratified analysis also included to assess the impact of race, gender, dosage and vitamin D blood serum levels.

The rationale behind the study is supported by the growing body of evidence cited in the Introduction, suggesting that low levels of vitamin D are associated with an increased risk of suicidal behavior. The methods are appropriate and the conclusions valid. There are only a few amendments that are suggested to improve clarity of the manuscript as currently written

Methods:

It seems from Table 1 that the pre- and post-matched control groups for Vitamin D2 and D3 were independent of each other (as the starting numbers are different). Statistically speaking, this is a benefit and should be noted in the methods.

Line 86. The authors should specify the vitamin D assays employed for blood measures (e.g. 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D or both etc.)

Lines 132-135. For the vitamin D blood serum subgroups, the variable ln{average daily dosage)} is very confusing, as the natural log of 0 is undefined (those with no daily Vit D (thus ln{0}). In lines 99-102, the authors describe weighting the average dose by the numbers of days supplies during the observation period, but this would still not seem to amend an undefined value for those with no vitamin D (the control groups). In which case, how were the controls employed in the subgroup analysis? A better description of this variable and how it was employed in the models would be very helpful.

Results:

Did the authors consider the condition of TBI as a potential covariate, give that in this veteran population TBI may be frequent, may differ between exposure groups, and could impact the outcomes of interest?

Do the authors have access to vitamin D blood levels after the onset of supplementation? As if so, analysis by those that reached sufficient levels, versus those with continued insufficiency and/or deficiency may be interesting.

Discussion:

Sentence starting “ A secondary analysis of these data by suggested…….” A word is missing here.

Final paragraph: Reference should be included in this paragraph starting from the sentence “Other trials included subjects with…..”.

Conclusion: Second line of paragraph- it would be better for the authors refer to the veterans by another definition, rather than “Patients”.

Table 1: There are some mistakes in the tables: (e.g. Table 1 age of the D3 post-matched controls; Table 2, 0-19 D2 cohort numbers of control N and treated N, do no sum to the total patient N). Checking of the tables is advised.

**********

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If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Nigel Bark

Reviewer #2: No

**********

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The Association between Vitamin D Serum Levels, Supplementation, and Suicide Attempts and Intentional Self-Harm

PONE-D-22-20954R1

Dear Dr. Gibbons,

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.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

James D. Clelland, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. 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

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. 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: I appreciate the authors' responses to my comments and alterations or corrections where appropriate. All were addressed.

Reviewer #2: The authors have been very responsive to the previous reviewers comments. This manuscript is now ready to be published.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Nigel Bark

Reviewer #2: No

**********