Home Uncategorized Using the attached template, critically appraise the following article.

Uncategorized

Using the attached template, critically appraise the following article.

Vetter et al. Association Between Rotating Night Shift Work and Risk of Coronary Heart Disease Among Women.

Rubric for Article Critique Reports

Week

– Assignments 4a and 4b

Assignment 4 (indicate 4a or 4b)

Part

Question

Answer

Points

Title

1.Title of the article, journal name, your name

Purpose/Research problem

a. What is the purpose of the study? Is it clearly identified? Is the research problem important?

2b. Identify the dependent variable(s)

2c. Identify the independent variable(s)

Literature review

3a. Are the cited sources relevant to the study?

3b. Does the literature review offer a balanced critical analysis of the literature?

3c. Are the cited studies recent?

Theoretical framework*

4a. Has a conceptual or theoretical framework been identified?

4b. If yes, is the framework adequately described?

Design and procedures

5a. Identify the study design used in this study? Make sure that you select the exact type of design used, i.e., one of the three discussed this week.

5b. Is the study design appropriate to answer the research question?

5c. What type of sampling design was used?

5d. Was the sample size justified on the basis of a power analysis or other rationale?

5e. Are the inclusion and exclusion criteria clearly identified? What are they?

5f. What measurement tools were used for the dependent variable(s)?

5g. What measurement tools were used for the independent variable(s)?

5h. Were validity and reliability issues discussed?

Ethical considerations

6a. Were the participants fully informed about the nature of the research?

6b. Were the participants protected from harm?

6c. Was ethical permission granted for the study?

Data analysis

7a. What type of data and statistical analysis was undertaken?

7b. Was the statistical analysis appropriate to address the research question?

Results

8. What are the results of the study? Did the results answer the research question(s)?

Discussion

9a. Were the findings linked back to the literature review?

9b. Did the authors identify study limitations? What were they?

9c. Do you think the limitations are serious enough to impact the internal and external validity** of the study?

Overall assessment

10. What is your overall assessment of the study?

Total

100

Source: Coughlan M, Cronin P, Ryan F. Step-by-step guide to critiquing research. Part 1: quantitative research. Br J Nurs. 2007;16(11):658-63.

* A conceptual or theoretical framework/model is a representation of a concept and the relationships between this concept and other variables that might impact it or be affected by it. It provides structure to a study and a rationale for the different relationships between the variables. Not every study has to have a conceptual or theoretical framework clearly outlined. The better research questions are usually the ones informed by theory and a corresponding framework. For an example, check the following article:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3934012/

** The validity of a study, in contrast to the validity of measurements, is the degree to which study results are accurate and well-founded, when account is taken of study methods, representativeness of study sample, and nature of the population from which it is drawn.

· Internal validity (results are attributed to hypothesized effect and not sample differences)

· External validity (generalizability)

Association Between Rotating Night Shift Work and Risk
of Coronary Heart Disease Among Women
Céline Vetter, PhD; Elizabeth E. Devore, ScD; Lani R. Wegrzyn, ScD; Jennifer Massa, ScD; Frank E. Speizer, MD;
Ichiro Kawachi, MD, ScD; Bernard Rosner, PhD; Meir J. Stampfer, MD, DrPH; Eva S. Schernhammer, MD, DrPH

IMPORTANCE Prospective studies linking shift work to coronary heart disease (CHD) have
been inconsistent and limited by short follow-up.

OBJECTIVE To determine whether rotating night shift work is associated with CHD risk.

DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study of 189 158 initially healthy
women followed up over 24 years in the Nurses’ Health Studies (NHS [1988-2012]:
N = 73 623 and NHS2 [1989-2013]: N = 115 535).

EXPOSURES Lifetime history of rotating night shift work (�3 night shifts per month in
addition to day and evening shifts) at baseline (updated every 2 to 4 years in the NHS2).

MAIN OUTCOMES AND MEASURES Incident CHD; ie, nonfatal myocardial infarction, CHD
death, angiogram-confirmed angina pectoris, coronary artery bypass graft surgery, stents,
and angioplasty.

RESULTS During follow-up, 7303 incident CHD cases occurred in the NHS (mean age at
baseline, 54.5 years) and 3519 in the NHS2 (mean age, 34.8 years). In multivariable-adjusted
Cox proportional hazards models, increasing years of baseline rotating night shift work was
associated with significantly higher CHD risk in both cohorts. In the NHS, the association
between duration of shift work and CHD was stronger in the first half of follow-up than in the
second half (P=.02 for interaction), suggesting waning risk after cessation of shift work.
Longer time since quitting shift work was associated with decreased CHD risk among ever
shift workers in the NHS2 (P<.001 for trend).

Baseline History of Rotating Night Shift Work P Value
for
TrendNone <5 y 5-9 y ≥10 y

NHS cohort

CHD incidence ratea 425.5 435.1 525.7 596.9

HR (95% CI)b 1 [Reference] 1.02 (0.97-1.08) 1.12 (1.02-1.22) 1.18 (1.10-1.26)

<.001

First half of follow-up

CHD incidence ratea 367.3 382.4 483.1 494.4

HR (95% CI)b 1 [Reference] 1.10 (1.01-1.21) 1.19 (1.03-1.39) 1.27 (1.13-1.42) <.001

Second half of
follow-up

CHD incidence ratea 436.6 424.8 520.7 556.2

HR (95% CI)b 1 [Reference] 0.98 (0.92-1.05) 1.08 (0.96-1.21) 1.13 (1.04-1.24) .004

NHS2 cohort

CHD incidence ratea 122.6 130.6 151.6 178.0

HR (95% CI)b 1 [Reference] 1.05 (0.97-1.13) 1.12 (0.99-1.26) 1.15 (1.01-1.32) .01
a Age-adjusted rates per 100 000 person-years.
b Multivariable-adjusted hazard ratio (HR).

CONCLUSIONS AND RELEVANCE Among women who worked as registered nurses, longer
duration of rotating night shift work was associated with a statistically significant but small
absolute increase in CHD risk. Further research is needed to explore whether the association
is related to specific work hours and individual characteristics.

JAMA. 2016;315(16):1726-1734. doi:10.1001/jama.2016.4454

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JAMA Report Video at
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Supplemental content at
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Author Affiliations: Author
affiliations are listed at the end of this
article.

Corresponding Author: Céline
Vetter, PhD, Channing Division of
Network Medicine, 181 Longwood
Ave, Boston, MA 02115 (celine.vetter
@channing.harvard.edu).

Research

Original Investigation

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S ocietal and economic demands push toward an in-crease of employees’ 24-hour availability in health caresettings as well as in service and security industries. The
resulting disruption of social and biological rhythms, occur-
ring especially during shift work, has been hypothesized to in-
crease chronic disease risk,1-5 and suggestive evidence sup-
ports an association between shift work and coronary heart
disease (CHD), metabolic disorders, and cancer.6

In 1995, Kawachi et al7 examined the association be-
tween rotating night shift work and CHD in the Nurses’ Health
Study (NHS) over 4 years of follow-up and reported a 51% sig-
nificant increase in CHD risk (nonfatal myocardial infarction
[MI] and CHD death) among women with more than 6 years
of rotating night shift work after multivariable adjustment
(incidence rate per 100 000 person-years, 156.1 compared with
75.4 among women who never worked night shifts). A recent
systematic meta-analysis reported a 24% elevated CHD risk
associated with most types of shift work but noted signifi-
cant heterogeneity in exposure assessment and study de-
signs across studies.8 The present study reassessed the asso-
ciation of rotating night shift work and coronary health in the
Nurses’ Health Studies (NHS and NHS2) with 24 years of
follow-up and examined manifestations of CHD (angiogram-
confirmed angina pectoris, coronary artery stents, angio-
plasty, and coronary artery bypass graft [CABG] surgery),
in addition to nonfatal MI and CHD death. Additionally, pos-
sible differences in this association over time, including ef-
fects of time since quitting shift work, were explored. The
study also examined the excess risk of CHD associated with
shift work among women without diabetes, hypertension, or
hypercholesterolemia—potential comorbid mediators of CHD.

Methods
Study Population
The NHS and NHS2 are ongoing, prospective cohort studies. The
NHS began in 1976 when 121 701 female registered US nurses
aged 30 to 55 years responded to a baseline questionnaire.9 The
NHS2 started in 1989 and included 116 430 female registered US
nurses aged 25 to 42 years. In both cohorts, biennial follow-up
questionnaires have been mailed to update information on
medical history, lifestyle factors, and newly diagnosed dis-
eases. Follow-up rates were high in both cohorts, with approxi-
mately 90% participation at each 2-year cycle. This study
was reviewed and approved by the Brigham and Women’s Hos-
pital Institutional Review Board; completion of the self-
administered questionnaire was considered informed con-
sent, so the requirement for oral or written consent was waived.

Rotating Night Shift Work Assessment
In the NHS, lifetime years of exposure to rotating night shift
work (defined as ≥3 night shifts per month, in addition to day
and evening shifts) was queried once, in 1988. In the NHS2,
women indicated in 1989 how many years of rotating night shift
work they had worked, with updates in 1991, 1993, 1997, 2001,
2005, and 2007; retrospective assessments for shift work in
1995, 1999, and 2003 were included on the 2001 and 2005

questionnaires, respectively. The analyses used baseline as-
sessments of lifetime shift work history in each cohort (1988
for NHS and 1989 for NHS2), as well as cumulative shift work
exposure through 2007 in the NHS2. In all analyses, night shift
work information was carried forward for 1 questionnaire cycle
in the case of missing data.

Ascertainment of CHD
On baseline and follow-up questionnaires, participants were
asked to report physician-diagnosed CHD events. Those who
reported nonfatal MI were asked for medical record access so
that exposure-blinded physicians could confirm self-reported
nonfatal MI. Nonfatal MI was confirmed using the World Health
Organization criteria, which required diagnostic electrocardio-
graphic findings or elevated enzyme levels in addition to typi-
cal symptoms.10 Participant deaths were identified through the
National Death Index, next of kin, or postal authorities, with pri-
mary cause of death being determined by autopsy reports, hos-
pital records, and death certificates. The primary outcome was
incident CHD, including self-reported cases of CABG surgery,
angina pectoris (confirmed by angiogram), angioplasty, and
coronary artery stents, in addition to nonfatal MI and CHD death
(including fatal MI), whichever came first. Secondary analyses
were restricted to nonfatal MI and CHD death.

Covariate Assessment
In both cohorts, biennial questionnaires were used to collect
information on medical history, anthropometric data, diet, and
lifestyle. Most variables were updated biennially from base-
line onward; physical activity and dietary data were obtained
approximately every 4 years. Dietary habits were assessed using
a semiquantitative, validated food frequency questionnaire11

calculating the Alternative Healthy Eating Index, which has pre-
viously been found to be a reliable predictor of CHD in these
cohorts.12 Parity was updated until 1996 and 2009 for the NHS
and NHS2, respectively, and subsequently carried forward. Par-
ticipants’ husbands’ educational attainment (a proxy for so-
cioeconomic status assessed in 1992 in NHS and in 1999 in
NHS2), family history of MI before age 60 years (1976 and 1984
in NHS and 1989, 1997, and 2001 in NHS2), and race (2004 in
NHS and 1989 and 2005 in NHS2) were not updated through-
out follow-up. Usual sleep duration assessed in 1986, 2000,
and 2008 (NHS) and 2001 (NHS2), and social support (assessed
by asking whether participants had a confidant) in 1992, 2000,
2004, and 2008 (NHS) and in 1993 (NHS2) were not regularly
updated throughout follow-up.

Statistical Analyses
Age- and multivariable-adjusted Cox proportional hazards
models were used to estimate hazard ratios (HRs) and 95%
confidence intervals across rotating night shift work catego-
ries (none, <5, 5-9, and ≥10 years). Women with no history of rotating night shift work comprised the reference category in all analyses. Calculations of P values for trend were based on the midpoint of rotating night shift work categories, with the highest category conservatively set to 10; the reported P value was based on the Wald test. The proportional hazards assump- tion was tested by including an interaction of shift work

Rotating Night Shift Work and Risk of CHD Among Women Original Investigation Research

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(ie, midpoint of categories) by time in all models, and its sig-
nificance was evaluated using the Wald statistic. In sensitiv-
ity analyses, the outcome was restricted to nonfatal MI and CHD
death. Additional sensitivity analyses were restricted to par-
ticipants with no baseline history of major comorbidities po-
tentially mediating CHD (ie, diabetes, hypertension, and hy-
percholesterolemia) and censored women who reported any
of these conditions throughout follow-up.

The following cardiovascular disease risk factors were in-
cluded in multivariable-adjusted models: family history of MI
before age 60 years, diet quality (Alternative Healthy Eating
Index,12 without the alcohol and multivitamin components, in
quintiles), physical activity (metabolic equivalent task–hours per
week, in quintiles), body mass index (BMI, calculated as weight
in kilograms divided by height in meters squared: <25, 25-29, 30-35, or >35), cumulative pack-years smoked (continuous), al-
cohol intake (none, 0.1-5, 5.1-10, 10.1-20, or >20 g/d), parity (nul-
liparous, 1, 2, or ≥3 children), menopausal status (premenopaus-
al or postmenopausal), hormone therapy (premenopausal, ever,
or never), race (white, black, or other), husband’s highest edu-
cational level (high school diploma or less, college degree, or
graduate school level or similar), multivitamin use (yes or no),
acetaminophen use (yes or no), nonsteroidal anti-inflammatory
drug use (yes or no), aspirin use (yes or no), hypertension (yes or
no), diabetes (yes or no), and hypercholesterolemia (yes or no).
In additional analyses, models were adjusted for sleep duration
(<6, 6-7, 8-9, or ≥10 hours per day) and social support (yes or no). Dummy variables were used to indicate missing covariate val- ues. For missing information on pack-years of smoking, the me- dian among smokers was imputed; in the case of missing BMI, information was carried forward once. On average, 9.5% of co- variate information was missing across 24 years of follow-up.

In the NHS2, analyses also examined the association be-
tween cumulative time since quitting rotating night shift work
(never, current, <12, 12-24, or >24 years) and CHD risk. Time since
quitting rotating night shift work was estimated based on life-
time reports of exposure in 1989 and updated shift work infor-
mation throughout follow-up. If women reported rotating night
shifts at baseline only, time since quitting shift work was esti-
mated by subtracting 21 years (assumed age at starting shift
work) and the lower bound of the categorically reported dura-
tion of rotating night shift work from their age in 1989.

In additional secondary analyses, potential effect modi-
fication by BMI (<25, 25-30, or >30) was examined, adjusting
continuously for BMI within each stratum. To evaluate poten-
tial interactions, the log likelihood ratio test was used to com-
pare models with and without cross-product interaction terms;
corresponding P values were based on χ2 statistics.

The a priori hypothesis was that rotating night shift work in-
creased CHD risk, and all secondary analyses were preplanned.
Analyses were conducted with SAS software, version 9.4 (SAS
Institute Inc) with a 2-sided significance threshold of P < .05.

Results
A total of 103 525 NHS participants answered the 1988 ques-
tionnaire. Of these, women with CHD, stroke, or cancer

(n = 14 065) and those who did not answer the shift work
question in 1988 (n = 15 837) were excluded, leaving 73 623
women for analysis. In the NHS2, 116 430 women answered
the baseline questionnaire (1989), of whom 895 reported
stroke or CHD prior to baseline, so that after the same exclu-
sions, 115 535 women were left for analysis. For the NHS2
analysis with updated shift work information, women who
did not answer shift work questions for 2 consecutive cycles
(on average, 8.7% per cycle) were censored. Women were
excluded from further follow-up after any self-reported
stroke, incident CHD, or death.

During 24 years of follow-up, a total of 10 822 incident CHD
cases were observed (7303 in NHS and 3519 in the younger
NHS2). Table 1 describes age and age-adjusted (within-
cohort) characteristics of the study population across catego-
ries of lifetime years of rotating night shift work at baseline.
Compared with women in the NHS, women in the NHS2 were
younger, more likely to be nulliparous, had slightly lower al-
cohol consumption, reported fewer pack-years of smoking, had
fewer comorbid conditions, and took fewer medications and
multivitamin supplements. With increasing duration of rotat-
ing night shift work, women were heavier in both cohorts. Also,
in the NHS, a lower proportion of women had husbands with
graduate-level education across increasing categories of shift
work, while pack-years of smoking and self-reports of hyper-
tension increased; in the NHS2, a greater proportion of nul-
liparous women and acetaminophen users were observed with
increasing duration of rotating night shift work.

Compared with women without a history of rotating night
shift work (incidence rates, 425.5 and 122.6 per 100 000 per-
son-years in the NHS and NHS2, respectively), women who
worked less than 5 years of shift work at baseline did not have
a significantly increased CHD risk in age-adjusted analyses
(Table 2 and Table 3), but there was a significant association
between longer durations of shift work and CHD risk (in the
NHS: incidence rate per 100 000 person-years for 5-9 years,
525.7; HR, 1.21 [95% CI, 1.11-1.33]; incidence rate for ≥10 years,
596.9; HR, 1.36 [95% CI, 1.27-1.46]; P<.001 for trend; in the NHS2: incidence rate for 5-9 years, 151.6; HR, 1.22 [95% CI, 1.08- 1.38]; incidence rate for ≥10 years, 178.0; HR, 1.34 [95% CI, 1.17- 1.53]; P<.001 for trend).

Multivariable adjustment for known CHD risk factors
attenuated these estimates, but the elevated risk observed
for 5 years or more of shift work persisted in the NHS (multi-
variable HR for 5-9 years, 1.12 [95% CI, 1.02-1.22]; multivari-
able HR for ≥10 years, 1.18 [95% CI, 1.10-1.26]; P<.001 for trend), and for 10 years or more of shift work in the NHS2 (multivariable HR for 5-9 years, 1.12 [95% CI, 0.99-1.26]; mul- tivariable HR for ≥10 years, 1.15 [95% CI, 1.01-1.32]; P = .01 for trend).

In the NHS, there was a significant interaction between
rotating night shift work exposure and time ( by 2-year
period, P<.001 for interaction) (Table 2), suggesting that CHD risk associated with shift work changes over time. During the first half of follow-up, higher effect estimates and signifi- cantly elevated risks also were observed with shorter dura- tions of shift work exposure (incidence rate per 100 000 person-years for <5 years, 382.4; multivariable HR, 1.10 [95%

Research Original Investigation Rotating Night Shift Work and Risk of CHD Among Women

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CI, 1.01-1.21]; incidence rate for 5-9 years, 483.1; multivariable
HR, 1.19 [95% CI, 1.03-1.39]; incidence rate for ≥10 years,
494.4; multivariable HR, 1.27 [95% CI, 1.13-1.42]; P < .001 for

trend and P = .02 for interaction for first vs second half of
follow-up). In the second half of follow-up, compared with
women who never worked rotating night shifts (incidence

Table 1. Age and Age-Adjusted Characteristics of Participating Women at Baseline by Rotating Night Shift Work Historya

Characteristics

Rotating Night Shift Work Exposure (≥3 Night Shifts Per Month)

NHS (1988) NHS2 (1989)
None
(n=30 012)

<5 y (n=30 122)

5-9 y
(n=4955)

≥10 y
(n=8534)

None
(n=43 657)

<5 y (n=56 179)

5-9 y
(n=9866)

≥10 y
(n=5833)

Age, mean (SD), y 54.0 (7.1) 54.3 (7.1) 54.9 (7.1) 56.2 (6.9) 34.8 (4.7) 34.5 (4.7) 35.1 (4.2) 37.1 (3.6)

White race, No. (%) 29 390 (98) 29 424 (98) 4832 (98) 8250 (97) 42 075 (96) 53 501 (95) 9337 (95) 5479 (95)

Parity,

No. (%)

Nulliparous 1434 (5) 1795 (6) 351 (7) 539 (6) 12 111 (28) 17 814 (31) 3440 (36) 1795 (37)

1 or 2 children 10 415 (34) 10 650 (35) 1761 (36) 2853 (35) 23 249 (53) 28 704 (51) 4889 (50) 2926 (48)

≥3 children 17 750 (60) 17 211 (57) 2743 (55) 4956 (57) 8290 (19) 9653 (18) 1536 (15) 1109 (16)

Parental history of MI
at age <60 y, No. (%)

4893 (16) 5081 (17) 879 (18) 1516 (18) 6105 (14) 8294 (15) 1670 (17) 1011 (16)

Body mass index,
mean (SD)b

25.2 (4.8) 25.4 (4.8) 26.0 (5.3) 26.6 (5.4) 23.9 (4.9) 24.0 (5.0) 24.8 (5.5) 25.1 (5.8)

No. (%)

<25 18 206 (61) 17 910 (59) 2683 (54) 4242 (50) 31 400 (72) 39 851 (71) 6365 (65) 3420 (62)

25-29.9 7926 (27) 8107 (27) 1455 (29) 2559 (30) 7693 (18) 10 300 (18) 2068 (21) 1330 (22)

30-34.9 2645 (9) 2877 (10) 545 (11) 1116 (13) 2837 (7) 3723 (7) 853 (9) 606 (9)

≥35 1235 (4) 1228 (4) 272 (6) 617 (7) 1727 (4) 2305 (4) 580 (6) 477 (7)

Pack-years of smoking,
median (IQR)c

18 (7-34) 18 (6-34) 20 (7-35) 24 (10-39) 10 (5-16) 9 (5-16) 10 (5-17) 11 (6-19)

Husband holds graduate
school degree, No. (%)

5841 (19) 6346 (21) 840 (17) 1028 (12) 9351 (21) 13 810 (25) 2079 (21) 1090 (18)

Alcohol intake, median
(IQR), g/dd

1.8 (0-7.6) 1.9 (0-8.3) 1.8 (0-7.3) 1.1 (0-6.2) 0.9 (0-3.1) 0.9 (0-3.7) 0.9 (0-3.6) 0.9 (0-2.9)

Alternative Healthy Eating
Index score (2010),
mean (SD)e

45.7 (10.5) 46.0 (10.4) 46.0 (10.3) 45.3 (10.1) 43.6 (10.5) 44.3 (10.5) 44.2 (10.4) 44.1 (10.3)

Physical activity, median
(IQR), MET-hours/wkf

7.9
(2.9-20.2)

9.1
(3.4-20.9)

9.0
(3.4-21.5)

8.4
(3.2-21.5)

12.3
(4.7-27.4)

14.6
(5.5-31.6)

15.1
(5.8-33.3)

14.2
(5.2-32.1)

Multivitamin use, No. (%) 18 518 (62) 19 011 (63) 3148 (64) 5325 (62) 23 704 (54) 30 053 (54) 5254 (53) 3242 (55)

Aspirin use, No. (%) 18 482 (62) 19 105 (63) 3122 (63) 5374 (63) 4747 (11) 6119 (11) 1195 (12) 827 (13)

NSAID use, No. (%) 9537 (31) 9680 (32) 1575 (32) 2728 (33) 7775 (18) 10 986 (20) 2206 (22) 1409 (22)

Acetaminophen use,
No. (%)g

11 110 (37) 11 315 (37) 1849 (38) 3204 (39) 9229 (21) 12 370 (22) 2292 (23) 1529 (26)

Postmenopausal,
No. (%)

20 735 (71) 21 254 (71) 3674 (72) 6866 (74) 965 (2) 1271 (2) 247 (2) 238 (3)

Current hormone therapy,
No. (%)

6833 (23) 7059 (24) 1122 (22) 1868 (21) 997 (2) 1263 (2) 246 (2) 236 (3)

Self-reported hypertension,
No. (%)

7464 (25) 7641 (26) 1448 (29) 2781 (30) 2270 (5) 2938 (5) 627 (6) 460 (7)

Self-reported diabetes,
No. (%)

1048 (4) 995 (3) 221 (4) 507 (6) 396 (1) 402 (1) 74 (1) 68 (1)

Self-reported
hypercholesterolemia,
No. (%)

6683 (23) 6837 (23) 1171 (23) 2781 (24) 4493 (10) 5809 (10) 1100 (11) 722 (11)

Usual sleep duration,
No. (%), hh

≤6 6978 (23) 7506 (25) 1427 (29) 2901 (34) 8939 (20) 12 230 (22) 2542 (26) 1670 (28)

7 11 299 (38) 11 353 (38) 1770 (36) 2609 (31) 13 835 (32) 17 397 (31) 2779 (28) 1552 (26)

8-9 7661 (26) 7358 (24) 1044 (21) 1709 (19) 9593 (22) 11 178 (20) 1680 (17) 892 (16)

≥10 157 (1) 132 (0) 24 (0) 56 (1) 245 (1) 322 (1) 52 (1) 37 (1)

Social support, No. (%)i 22 288 (94) 22 667 (94) 3617 (93) 6019 (94) 31 370 (94) 39 389 (95) 6822 (95) 3930 (94)

Abbreviations: IQR, interquartile range; MET, metabolic equivalent task; MI,
myocardial infarction; NHS, Nurses’ Health Study; NSAID, nonsteroidal
anti-inflammatory drug.
a Numbers that do not add up to 100% are attributable to missing data.
b Calculated as weight in kilograms divided by height in meters squared.
c Cumulative among smokers.
d Assessed in 1986 for the NHS and in 1991 for the NHS2.

e Assessed in 1986 for the NHS and in 1991 for the NHS2. Higher scores reflect a
healthier diet.12

f Weekly energy expenditure in MET-hours from recreational and leisure time
activities.

g Assessed in 1990 for the NHS and in 1989 for the NHS2.
h Assessed in 1986 for the NHS and in 2001 for the NHS2.
i Assessed in 1992 for the NHS and in 1993 for the NHS2.

Rotating Night Shift Work and Risk of CHD Among Women Original Investigation Research

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rate per 100 000 person-years, 436.6), only those who
worked 10 years or more of shift work had a significantly
elevated CHD risk (incidence rate, 556.2; multivariable HR,
1.13 [95% CI, 1.04-1.24]; P = .004 for trend). The association
between shift work and CHD risk was not significant in the
last 4 years of follow-up (2008-2012; incidence rate for <5 years, 219.9; multivariable HR, 0.85 [95% CI, 0.70-1.03]; inci- dence rate for 5-9 years, 247.2; multivariable HR, 0.88 [95%

CI, 0.62-1.26]; incidence rate for ≥10 years, 306.3; multivari-
able HR, 1.04 [95% CI, 0.80-1.35]; P = .94 for trend) (eTable 1
in the Supplement).

All categories of rotating night shift work showed a sig-
nificantly elevated CHD risk when shift work history was
cumulatively updated in the NHS2 (inc idence rate per
100 000 person-years for <5 years, 137.4; multivariable HR, 1.12 [95% CI, 1.01-1.24]; incidence rate for 5-9 years, 161.9;

Table 2. Shift Work and Risk of Coronary Heart Disease in the NHSa

Cohort

Baseline History of Rotating Night Shift Workb
P Value for
Trendc

P Value for
Interaction, Shift
Work × TimedNone <5 y 5-9 y ≥10 y

Overall NHS, 1988 to 2012

Cases/person-years 2739/643 774 2857/644 857 568/103 574 1139/173 571

Incidence rate per 100 000 person-years (95% CI)e 425.5
(383.9-467.1)

435.1
(392.8-477.5)

525.7
(410.4-641.1)

596.9
(502.1-691.7)

Age-adjusted model, HR (95% CI) 1 [Reference] 1.02
(0.96-1.07)

1.21
(1.11-1.33)

1.36
(1.27-1.46)

<.001

Multivariable-adjusted model, HR (95% CI)f 1 [Reference] 1.02
(0.97-1.08)

1.12
(1.02-1.22)

1.18
(1.10-1.26)

<.001 <.001

First vs second half of follow-up .02

June 1988 to May 2000

Cases/person-years 915/351 568 1021/352 490 213/57 612 455/97 899

Incidence rate per 100 000 person-years (95% CI)e 367.3
(302.4-432.3)

382.4
(316.8-448.1)

483.1
(306.6-659.7)

494.4
(370.1-618.8)

Multivariable-adjusted model, HR (95% CI)f 1 [Reference] 1.10
(1.01-1.21)

1.19
(1.03-1.39)

1.27
(1.13-1.42)

<.001 .03

June 2000 to May 2012

Cases/person-years 1824/305 036 1836/305 297 355/48 238 684/79 819

Incidence rate per 100 000 person-years (95% CI)e 436.6
(367.8-505.4)

424.8
(361.8-487.7)

520.7
(377.1-664.3)

556.2
(414.2-754.3)

Multivariable-adjusted model, HR (95% CI)f 1 [Reference] 0.98
(0.92-1.05)

1.08
(0.96-1.21)

1.13
(1.04-1.24)

.004 .08

Restricted to myocardial infarction and coronary heart
disease death

June 1988 to May 2000

Cases/person-years 443/353 659 491/354 846 117/58 026 226/99 022

Incidence rate per 100 000 person-years (95% CI)e 173.0
(128.3-217.8)

182.3
(137.2-227.4)

276.2
(142.6-409.9)

236.5
(151.8-321.3)

Multivariable-adjusted model, HR (95% CI)f 1 [Reference] 1.12
(0.99-1.28)

1.35
(1.10-1.66)

1.29
(1.09-1.51)

.001 .19

June 2000 to May 2012

Cases/person-years 444/316 989 428/318 083 65/50 714 176/84 689

Incidence rate per 100 000 person-years (95% CI)e 106.6
(73.1-140.0)

92.3
(69.1-115.5)

101.5
(36.4-166.5)

133.3
(76.4-190.1)

Multivariable-adjusted model, HR (95% CI)f 1 [Reference] 0.95
(0.83-1.09)

0.77
(0.60-1.00)

1.09
(0.91-1.30)

.84 .56

Abbreviations: HR, hazard ratio; NHS, Nurses’ Health Study.
a A total of 7303 coronary heart disease cases (ie, nonfatal myocardial infarction,

coronary heart disease–attributed death, angiogram-confirmed angina pectoris,
angioplasty, coronary artery bypass graft surgery, and coronary artery stents)
occurred during 24 years of follow-up in the NHS (N = 73 623).

b Assessed in 1988.
c Based on category midpoints, except for �10 years, for which the midpoint

was set to 10 years.
d Based on the interaction between shift work category midpoints (except for

�10 years, for which the midpoint was set to 10 years) and time
(in 2-year cycles).

e Incidence rates and 95% CIs are adjusted to the age distribution of
women who reported no history of rotating night shift work,
separately for each cohort.

f Multivariable-adjusted model included age, physical activity (metabolic
equivalent task–hours per week, in quintiles), diet (Alternative Healthy Eating
Index score,12 in quintiles), alcohol consumption (none, 0.1-5, 5.1-10,
10.1-20, or >20 g/d), pack-years of smoking (continuous), parental history
of myocardial infarction prior to age 60 years (yes or no), menopausal status
(premenopausal vs postmenopausal), parity (nulliparous, 1 child, 2 children,
or �3 children), hormone therapy (ever, never, or premenopausal),
multivitamin use (yes or no), acetaminophen use (yes or no), nonsteroidal
anti-inflammatory drug use (yes or no), aspirin use (yes or no), hypertension
(yes or no), hypercholesterolemia (yes or no), diabetes (yes or no),
body mass index (<25, 25-29.9, 30-34.9, or �35), race (white, black, or other), and husband’s highest educational level (up to high school diploma, college degree, or graduate school or similar).

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multivariable HR, 1.19 [95% CI, 1.04-1.37]; incidence rate for
≥10 years, 190.5; multivariable HR, 1.27 [95% CI, 1.09-1.48];
P<.001 for trend) (Table 3), compared with women without a history of rotating night shift work (incidence rate, 115.8). In the NHS2, CHD risk also decreased with increasing time since quitting shift work (P<.001 for trend) (eTable 2 in the Supplement).

When analyses were restricted to MI and CHD deaths, over-
all, results were similar in the NHS (Table 2) but were attenu-
ated in the NHS2 (Table 3). Results remained largely un-
changed with further adjustment for sleep duration and social
support (eTable 3 in the Supplement).

In women without a history of diabetes, hypertension, or
elevated cholesterol levels, there was a significant trend of
increased CHD risk with longer duration of shift work in the
NHS (P = .004 for trend) (Table 4) but not in the NHS2 (P = .11
for trend).

In analyses stratified by BMI, a significant dose-response
relationship between shift work and CHD risk across all BMI
categories in the NHS was observed (eTable 4 in the Supple-
ment), with highest estimates among obese women (test for

interaction, 10.9; P = .05). In the NHS2, there was a signifi-
cant dose-response relationship between shift work and CHD
risk only in obese women (P = .002 for trend) but not in normal-
weight or overweight women (P=.53 and P=.47 for trend for
normal-weight and overweight women, respectively); the in-
teraction between shift work and BMI was not significant (test
for interaction, 10.4; P = .06).

Discussion
This prospective cohort study examined the association of ro-
tating night shift work with CHD incidence over 24 years of
follow-up and found that 5 years or more of rotating night shift
work was associated with a significantly increased risk of CHD.
The results suggest that recent shift work might be most rel-
evant, as significantly stronger associations were observed in
the first vs second part of follow-up in the NHS (27% vs 13%
increased risk for ≥10 years of rotating night shift work expo-
sure), in addition to an association between decreasing CHD
risk with increasing time since quitting shift work in the NHS2.

Table 3. Shift Work and Risk of Coronary Heart Disease in the NHS2a

Cohort

Rotating Night Shift Work Exposure
P Value for
Trendb

P Value for
Interaction, Shift
Work × TimecNone <5 y 5-9 y ≥10 y

Baseline history of shift workd

Cases/person-years 1236/1 007 860 1673/1 296 585 347/226 580 263/132 971

Incidence rate per 100 000 person-years
(95% CI)e

122.6
(105.0-140.3)

130.6
(114.5-146.7)

151.6
(109.2-194.0)

178.0
(123.0-234.0)

Age-adjusted model, HR (95% CI) 1 [Reference] 1.06
(0.99-1.14)

1.22
(1.08-1.38)

1.34
(1.17-1.53)

<.001

Multivariable-adjusted model, HR (95% CI)f 1 [Reference] 1.05
(0.97-1.13)

1.12
(0.99-1.26)

1.15
(1.01-1.32)

.01 .54

Restricted to myocardial infarction and coronary
heart disease death

Cases/person-years 151/1 018 680 161/1 311 173 38/229 694 35/135 197

Incidence rate per 100 000 person-years
(95% CI)e

14.8
(9.5-20.2)

12.4
(7.9-16.9)

16.2
(4.3-28.0)

24.4
(7.2-41.6)

Multivariable-adjusted model, HR (95% CI)f 1 [Reference] 0.83
(0.66-1.04)

0.98
(0.69-1.41)

1.09
(0.75-1.59)

.71 .55

Updated shift workg

Cases/person-years 589/554 846 1077/872 476 328/222 286 233/118 813

Incidence rate per 100 000 person-years
(95% CI)e

115.8
(91.2-140.4)

137.4
(116.2-158.6)

161.9
(116.3-207.6)

190.5
(125.1-255.8)

Age-adjusted model, HR (95% CI) 1 [Reference] 1.18
(1.06-1.30)

1.40
(1.22-1.61)

1.59
(1.36-1.85)

<.001

Multivariable-adjusted model, HR (95% CI)f 1 [Reference] 1.12
(1.01-1.24)

1.19
(1.04-1.37)

1.27
(1.09-1.48)

.001 .84

Abbreviations: HR, hazard ratio; NHS, Nurses’ Health Study.
a A total of 3519 coronary heart disease cases (ie, nonfatal myocardial infarction,

coronary heart disease–attributed death, angiogram-confirmed angina
pectoris, angioplasty, coronary artery bypass graft surgery, and coronary
artery stents) occurred during 24 years of follow-up in the NHS2 (N = 115 535).

b Based on category midpoints, except for �10 years, for which the midpoint
was set to 10 years.

c Based on the interaction between shift work category midpoints (except for
�10 years, for which the midpoint was set to 10 years) and time
(in 2-year cycles).

d Assessed in 1989.
e Incidence rates and 95% CIs are standardized relative to the age distribution

of women who reported no history of rotating night shift work, separately for
each cohort.

f Multivariable-adjusted model including age, physical activity (metabolic
equivalent task–hours per week, in quintiles), diet (Alternative Healthy Eating
Index score,12 in quintiles), alcohol consumption (none, 0.1-5, 5.1-10,
10.1-20, or >20 g/d), pack-years of smoking (continuous), parental history of
myocardial infarction prior to age 60 years (yes or no), menopausal status
(premenopausal vs postmenopausal), parity (nulliparous, 1 child, 2 children,
or �3 children), hormone therapy (ever, never, or premenopausal),
multivitamin use (yes or no), acetaminophen use (yes or no), nonsteroidal
anti-inflammatory drug use (yes or no), aspirin use (yes or no), hypertension
(yes or no), hypercholesterolemia (yes or no), diabetes (yes or no),
body mass index (<25, 25-29.9, 30-34.9, or �35), race (white, black, or other), and husband’s highest educational level (up to high school diploma, college degree, or graduate school level or similar).

g Updated shift work refers to cumulative duration of rotating night shift work
reported up to 2007.

Rotating Night Shift Work and Risk of CHD Among Women Original Investigation Research

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In this younger cohort, when using cumulatively updated shift
work history, a higher CHD risk was observed, with 12%, 19%,
and 27% increased risk for less than 5 years, 5 to 9 years, and
10 years or more of shift work, respectively. Results were simi-
lar overall when restricting to women without hypertension,
diabetes, or hypercholesterolemia, suggesting that these con-
ditions may not be the prime mediators of observed associa-
tions between shift work and CHD. In summary, the present
analysis indicated that rotating night shift work was associ-
ated with increased CHD risk in a duration-dependent man-
ner and that this risk waned over time.

Results were consistent with a recent meta-analysis that
found a 24% increased risk of “any coronary event” in shift
workers despite significant heterogeneity detected across 28
studies, presumably due to heterogeneous outcome and ex-
posure definitions.8 The present study was based on a defini-
tion of rotating night shift work (≥3 night shifts per month) that
has been used extensively in existing literature, although it did
not incorporate more precise intensity measures related to fre-
quency and actual working times.13,14

Lifetime history of rotating night shift work was queried
on average at age 55 years in the NHS, when women are less
likely to begin new shift work schedules; in the NHS2, women
were asked about shift work history when they were in their
mid-30s, with updated shift work assessments throughout
follow-up. In the NHS, CHD risk associated with rotating night
shift work seemed to wane over time, so that after 20 years of

follow-up, the CHD risk associated with 10 years or more of ex-
posure was not significantly elevated. In 1995, Kawachi et al7

reported that 6 years or more of rotating shift work was asso-
ciated with 51% increased CHD risk after multivariable adjust-
ment, based on 4 years of follow-up and 292 CHD cases in the
NHS. The absolute incidence rate difference corresponded to
86.2 per 100 000 person-years (comparing never shift work-
ers with women with a history of ≥10 years of rotating night
shift work) and was of modest magnitude. The rate differ-
ence was also comparable with the one reported in the pres-
ent analysis, when restricting to the primary end points of
Kawachi and colleagues (ie, MI and CHD death) and the first
12 years of follow-up in the NHS (crude absolute incidence rate
difference, 91.6).

Concomitantly, higher risk estimates for updated shift work
were observed in the NHS2, and this CHD risk significantly de-
creased with increasing time since quitting shift work, lend-
ing further support to the suggestion that recent shift work was
particularly relevant for CHD risk—a new finding that war-
rants replication. Overall, the relative CHD risk associated with
rotating night shift work was statistically significant. How-
ever, the increased CHD risk was found in a small group of
women, those who worked 5 or more years on rotating night
shifts (only 15% of all women in the study population). Hence,
the absolute risk and public health impact of night work—
given confirmation of those results—would therefore be small.
Nonetheless, because changes in shift work schedules poten-

Table 4. Shift Work and Risk of Coronary Heart Disease in Women Without Diabetes, Hypertension, or Hypercholesterolemiaa

Cohort
Baseline History of Rotating Night Shift Workb
P Value for
Trendc
P Value for
Interaction, Shift
Work × TimedNone <5 y 5-9 y ≥10 y

NHS, 1988-2012

Cases/person-years 723/319 135 791/316 198 157/47 860 260/75 528

Incidence rate per 100 000 person-years
(95% CI)e

301.4
(243.5-359.2)

323.7
(263.0-384.4)

409.4
(238.3-580.5)

380.0
(255.1-504.9)

Age-adjusted model, HR (95% CI) 1 [Reference] 1.06
(0.96-1.18)

1.37
(1.15-1.63)

1.36
(1.17-1.57)

<.001

Multivariable-adjusted model, HR (95% CI)f 1 [Reference] 1.08
(0.97-1.19)

1.29
(1.08-1.54)

1.17
(1.01-1.36)

.004 .24

NHS2, 1989-2013

Cases/person-years 720/748 075 1001/966 924 193/165 593 134/92 148

Incidence rate per 100 000 person-years
(95% CI)e

100.6
(81.1-120.2)

112.1
(93.6-130.7)

122.9
(74.3-171.5)

136.8
(78.8-194.9)

Age-adjusted model, HR (95% CI) 1 [Reference] 1.09
(0.99-1.20)

1.17
(1.00 -1.38)

1.28
(1.06-1.54)

.003

Multivariable-adjusted model, HR (95% CI)f 1 [Reference] 1.09
(0.99-1.20)

1.10
(0.94 -1.30)

1.13
(0.94 -1.36)

.11 .78

Abbreviations: HR, hazard ratio; NHS, Nurses’ Health Study.
a All women who reported any of those comorbidities at baseline or throughout

follow-up were excluded from those analyses, both in the NHS (N = 43 557)
and the NHS2 (N = 98 126).

b Assessed in 1988 for the NHS and in 1989 for the NHS2.
c Based on category midpoints, except for �10 years, for which the midpoint

was set to 10 years.
d Based on the interaction between shift work category midpoints (except for
�10 years, for which the midpoint was set to 10 years) and time
(in 2-year cycles).

e Incidence rates and 95% CIs are standardized to the age distribution of
women who reported no history of rotating night shift work, separately for
each cohort.

f Multivariable-adjusted model including age, physical activity (metabolic
equivalent task–hours per week, in quintiles), diet (Alternative Healthy Eating
Index score,12 in quintiles), alcohol consumption (none, 0.1-5, 5.1-10,
10.1-20, or >20 g/d), pack-years of smoking (continuous), parental history of
myocardial infarction prior to age 60 years (yes or no), menopausal status
(premenopausal vs postmenopausal), parity (nulliparous, 1 child, 2 children,
or �3 children), hormone therapy (ever, never, or premenopausal),
multivitamin use (yes or no), acetaminophen use (yes or no), nonsteroidal
anti-inflammatory drug use (yes or no), aspirin use (yes or no),
body mass index (<25, 25-29.9, 30-34.9, or �35), race (white, black, or other), and husband’s highest educational level (up to high school diploma, college degree, or graduate school level or similar).

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tially could reduce such risk, it is important to further explore
the relationship between shift schedules and CHD risk.

In this study, the CHD outcomes examined reflect trends
in CHD care15,16 and included CABG surgery, angiogram-
confirmed angina pectoris, angioplasty, and stents in addition
to MI and CHD death. As stated by Hoffmann,17 an MI repre-
sents a relatively late stage of a long, ongoing disease process18;
to capture earlier manifestations of CHD, the outcome defini-
tion also encompassed angiogram-confirmed angina pectoris
and angioplasty. The analyses demonstrated a significant dose-
response relationship between rotating night shift work expo-
sure and this more comprehensive CHD outcome. In the NHS,
results were similar when restricting analyses to MI and CHD
death—the end points most other studies have examined. In the
NHS2, associations were no longer statistically significant when
analyses were restricted to MI and CHD death. There were many
fewer cases—only 1 in 10 cases was an MI or CHD death—thus,
there was less power to detect a significant association. Age dif-
ferences between the 2 cohorts (mid-50s in the NHS vs mid-
30s in the NHS2 at baseline in 1988 and 1989, respectively) and
technological advances resulting in different standards of care16

may explain these findings. The findings also suggest the im-
portance of evaluating a broader CHD end point in relation to
shift work, as part of the association could otherwise be con-
cealed by secondary and tertiary prevention.

Whether shift work was associated with increased CHD risk
in the absence of hypertension, hypercholesterolemia, and dia-
betes was another question of this study. A previous study
found no association between CHD-related disability and mor-
tality over 22 years in shift workers vs day workers after ex-
cluding individuals with cancer, angina pectoris, nonfatal MI,
obstructive pulmonary disease, hypertension, or diabetes
mellitus prior to baseline.19 In this study, when participants
with hypertension, elevated cholesterol levels, or diabetes were
excluded at baseline and throughout follow-up, a significant
dose-response relationship between rotating night shift work
and CHD risk was observed in the NHS but not in the NHS2.
Overall, this analysis supported the hypothesis that shift work
per se—and the associated disruption of biological and social
rhythms—could have increased CHD risk, even in the ab-
sence of or with only subclinical manifestations of poten-
tially mediating comorbidities such as hypertension, hyper-
cholesterolemia, or diabetes.

Obesity has been associated with a higher risk of CHD,20,21

such as MI and CHD death.22 All analyses were therefore ad-
justed for BMI (updated throughout follow-up), and additional
analyses examined whether the effects of shift work varied by
BMI. There was suggestive evidence for effect modification by
BMI. Although these results warrant replication, women who
were overweight might have been at an even higher risk of CHD
if they simultaneously worked rotating night shifts. Residual con-
founding by BMI could be an alternate explanation; however, as
analyses were adjusted for BMI continuously in each stratum,
this appeared a less likely explanation.

In the past 2 decades, sleep disturbances, psychosocial
stress, and social isolation have been identified as important
contributors to CHD risk.23-27 Therefore, additional analyses
adjusted for sleep and social support, and results remained

largely unchanged. However, given that shift work may affect
both sleep and social support,4 further research in popula-
tions with more extensive information on sleep duration, qual-
ity, and timing as well as work hours seems warranted. In ad-
dition, c irc adian misalignment—where the biologic al,
endogenous rhythm is asynchronous with behavioral cycles
of activity, sleep, and food intake—may be a key mechanism
linking shift work to chronic disease,28,29 including cardiovas-
cular disease.2,3,30 Future studies might also explore whether
an individual’s endogenous biological rhythm (also referred
to as chronotype)31 alters the association between lifetime his-
tory of rotating night shift and CHD risk, as early chronotypes
experience higher levels of circadian misalignment and sleep
curtailment during night shifts32 and might therefore show
higher CHD risk related to rotating night shift work.

This study has several strengths of note. It is large, with
more than 10 000 incident CHD cases over 24 years of follow-
up, and MI and CHD death were confirmed by medical and
death records. Detailed information on a wide range of poten-
tial confounding factors was available, and most of them were
updated regularly throughout follow-up. This study was also
based on one of the few cohorts with detailed lifetime shift
work exposure information.

Several limitations are also noteworthy. Conclusions can
be generalized to women only, and health effects of shift work
and pathways may be different in men and women.33 As in all
observational studies, even though known potential confound-
ing factors were controlled for, confounding due to unmea-
sured differences in behaviors or other factors may still exist.
This study relied on self-reports for angiogram confirmed an-
gina pectoris, CABG surgery, angioplasty and stents, but vali-
dation studies have demonstrated a high accuracy of self-
reports from these participants, all of whom are registered
nurses.34,35 The exposure assessments lacked information on
intensity of night shift work and physiological measures that
may be affected by shift work. Additionally, as information on
permanent night shift work over time was not collected,
women with such schedules might have been included in the
reference group. If permanent night shift workers had a higher
CHD risk compared with never rotating shift workers, this
would have biased results toward the null. Future studies
should include a more detailed assessment of work hours and
job demands, ideally in conjunction with chronotype and sleep
timing measures, to enable more detailed studies of circa-
dian strain on coronary health.14 Furthermore, studying CHD-
related biomarkers (eg, triglycerides, cholesterol levels, ca-
rotid plaque, or hemoglobin A1c)17,36 might be useful in
understanding underlying mechanisms.

Conclusions
Among women who worked as registered nurses, longer
duration of rotating night shift work was associated with a
statistically significant but small absolute increase in CHD
risk. Further research is needed to explore whether the
association is related to specific work hours and individual
characteristics.

Rotating Night Shift Work and Risk of CHD Among Women Original Investigation Research

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ARTICLE INFORMATION

Author Affiliations: Channing Division of Network
Medicine, Department of Medicine, Brigham and
Women’s Hospital and Harvard Medical School,
Boston, Massachusetts (Vetter, Devore, Speizer,
Rosner, Stampfer, Schernhammer); Department of
Epidemiology, Harvard T. H. Chan School of Public
Health, Boston, Massachusetts (Wegrzyn,
Stampfer, Schernhammer); Department of
Nutrition, Harvard T. H. Chan School of Public
Health, Boston, Massachusetts (Massa, Stampfer);
Department of Environmental Health, Harvard T. H.
Chan School of Public Health, Boston,
Massachusetts (Speizer); Department of Social and
Behavioral Sciences, Harvard T. H. Chan School of
Public Health, Boston, Massachusetts (Kawachi);
Department of Biostatistics, Harvard T. H. Chan
School of Public Health, Boston, Massachusetts
(Rosner); Department of Epidemiology, Center for
Public Health, Medical University of Vienna, Vienna,
Austria (Schernhammer).

Author Contributions: Dr Vetter had full access to
all of the data in the study and takes responsibility
for the integrity of the data and the accuracy of the
data analysis.
Study concept and design: Vetter, Speizer, Stampfer,
Schernhammer.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Vetter, Schernhammer.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Vetter, Devore, Wegrzyn, Massa,
Rosner, Schernhammer.
Obtained funding: Speizer, Schernhammer.
Administrative, technical, or material support:
Speizer, Schernhammer.
Study supervision: Rosner, Stampfer,
Schernhammer.

Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest and
none were reported.

Funding/Support: This research was supported by
Centers for Disease Control and Prevention/
National Institute for Occupational Safety and
Health grants 5R01OH009803 (to Dr
Schernhammer), UM1CA186107, UM1CA176726,
and R01HL034594. Dr Vetter was additionally
supported by a fellowship from the German
Research Foundation (VE 835/1-1).

Role of the Funder/Sponsor: The sponsor had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; or decision to submit
the manuscript for publication.

Additional Contributions: We thank the
participants and staff of the Nurses’ Health Study
cohorts for their valuable contributions. In addition,
we also thank Stephanie E. Chiuve, ScD
(Harvard T. H. Chan School of Public
Health and Harvard Medical School, Boston),
for helpful discussions, as well as Jeffrey
Pierre-Paul, PharmD, RPh (Massachusetts College
of Pharmacy and Health Sciences), for his support
in the early stages of the project. Participants did
not receive compensation, and staff were not
compensated outside of their salaries.

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