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Figure.
Life Expectancy (LE) With and Without Cardiovascular Disease (CVD) at Age 50 Years Among Thyrotropin and Free Thyroxine Tertiles, in Men and Women
Life Expectancy (LE) With and Without Cardiovascular Disease (CVD) at Age 50 Years Among Thyrotropin and Free Thyroxine Tertiles, in Men and Women
Table 1.  
Baseline Characteristics of 7785 Participants
Baseline Characteristics of 7785 Participants
Table 2.  
HRs for Incident Cardiovascular Disease (CVD) and Death Among Thyrotropin and Free Thyroxine (FT4) Tertiles
HRs for Incident Cardiovascular Disease (CVD) and Death Among Thyrotropin and Free Thyroxine (FT4) Tertiles
Table 3.  
Life Expectancy (LE) at 50 Years Among Thyrotropin and Free Thyroxine (FT4) Tertiles, in Men and Womena
Life Expectancy (LE) at 50 Years Among Thyrotropin and Free Thyroxine (FT4) Tertiles, in Men and Womena
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Original Investigation
November 2017

Association of Thyroid Function With Life Expectancy With and Without Cardiovascular Disease: The Rotterdam Study

Author Affiliations
  • 1Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
  • 2Academic Center for Thyroid Diseases, Erasmus Medical Center, Rotterdam, the Netherlands
  • 3Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
  • 4Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
  • 5Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
  • 6Section of Geriatric Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
JAMA Intern Med. 2017;177(11):1650-1657. doi:10.1001/jamainternmed.2017.4836
Key Points

Question  Are there differences in total life expectancy and life expectancy with and without cardiovascular disease within the reference range of thyroid function?

Findings  This population-based cohort study found significant differences in life expectancy within the reference range of thyroid function. After age 50 years, individuals with low-normal thyroid function lived longer overall and longer without cardiovascular disease than individuals with high-normal thyroid function.

Meaning  These findings provide supporting evidence for a reevaluation of current reference ranges of thyroid function and can help inform preventive and clinical care.

Abstract

Importance  Variations in thyroid function within reference ranges are associated with an increased risk of cardiovascular disease (CVD) and mortality. However, the impact of thyroid function on life expectancy (LE) and the number of years lived with and without CVD remains unknown.

Objective  To investigate the association of thyroid function with total LE and LE with and without CVD among euthyroid individuals.

Design, Setting, and Participants  The Rotterdam Study, a population-based, prospective cohort study. We included participants without known thyroid disease and with thyrotropin and free thyroxine (FT4) levels within the reference ranges.

Main Outcomes and Measures  Multistate life tables were used to calculate total LE and LE with and without CVD among thyrotropin and FT4 tertiles. Life expectancy estimates in men and women aged 50 years and older were obtained using prevalence, incidence rates, and hazard ratios for 3 transitions (healthy to CVD, healthy to death, and CVD to death), adjusting for sociodemographic and cardiovascular risk factors.

Results  The mean (SD) age of the 7785 participants was 64.7 (9.8) years, and 52.5% were women. Over a median follow-up of 8.1 (interquartile range, 2.7-9.9) years, we observed 789 incident CVD events and 1357 deaths. Compared with those in the lowest tertile, men and women in the highest thyrotropin tertile lived 2.0 (95% CI, 1.0 to 2.8) and 1.4 (95% CI, 0.2 to 2.4) years longer, respectively, of which, 1.5 (95% CI, 0.2 to 2.6) and 0.9 (95% CI, −0.2 to 2.0) years longer without CVD. Compared with those in the lowest tertile, the difference in life expectancy for men and women in the highest FT4 tertile was −3.2 (95% CI, −5.0 to −1.4) and −3.5 (95% CI, −5.6 to −1.5) years, respectively, of which, −3.1 (95% CI, −4.9 to −1.4) and −2.5 (95% CI, −4.4 to −0.7) years without CVD.

Conclusions and Relevance  At the age of 50 years, participants with low-normal thyroid function live up to 3.5 years longer overall and up to 3.1 years longer without CVD than participants with high-normal thyroid function. These findings provide supporting evidence for a reevaluation of the current reference ranges of thyroid function and can help inform preventive and clinical care.

Introduction

Thyroid dysfunction is one of the most common endocrine disorders.1 Clinical thyroid dysfunction is characterized by thyrotropin and free thyroxine (FT4) levels outside the reference ranges, whereas subclinical thyroid dysfunction is characterized by thyrotropin levels outside the reference range combined with FT4 levels within the reference range. At present, the reference ranges for thyrotropin and FT4 levels are statistically determined on the basis of the 2.5th and 97.5th percentiles of an apparently healthy population. This arbitrary approach, however, has been recently challenged by studies suggesting that the current reference ranges of thyroid function may need to be reevaluated by additionally taking into account the risk of clinical outcomes.2-5 In view of the ongoing debate on redefining the reference ranges of thyrotropin and FT4 levels, there is a need for novel insights about the qualitative and quantitative effect of thyroid function on an individual’s life and health.

The cardiovascular system represents a major target of thyroid hormone action.6 Both clinical and subclinical thyroid dysfunction have been associated with an increased risk of coronary heart disease,7,8 heart failure,9 and mortality.7,8,10,11 These deleterious effects of thyroid dysfunction might also be extended to the euthyroid range. Many studies conducted in middle-aged and elderly euthyroid individuals have reported an increased risk of cardiovascular disease (CVD) and mortality with lower thyrotropin and/or higher FT4 levels.2-5,12-16 Other studies do not find an association,17-19 probably due to the relatively small proportion of events,17,18 insufficient sample sizes,19 or short-term follow-up.17 However, it remains unclear whether there are meaningful differences in the remaining years of life lived with and without CVD for individuals within the reference range of thyroid function. Therefore, in a large population of euthyroid participants, we aimed to investigate the association of thyroid function with total life expectancy (LE) and LE with and without CVD.

Methods
Study Population

This study was embedded within the Rotterdam Study, a large prospective population-based cohort study. The objectives and design have been described in detail previously.20 The Rotterdam Study was initiated in 1989, including 7983 participants 55 years or older. In 2000, the study was extended with a second cohort of 3011 participants. In 2006, a third cohort of 3932 participants 45 years or older was added. Study participants undergo extensive follow-up medical examinations every 3 to 5 years. We included 7785 participants without known thyroid disease, with thyrotropin and FT4 levels within the reference range, and follow-up data on CVD events and deaths. Detailed information on the selection of study participants is provided in the eMethods and eFigure in the Supplement.

The protocols of the Rotterdam Study have been approved by the Medical Ethics Committee of Erasmus University and by the Ministry of Health, Welfare, and Sport of the Netherlands, implementing the Population Study Act Rotterdam Study. In accordance with the Declaration of Helsinki, all included participants provided written informed consent to participate in the study and to obtain information from their treating physicians.

Assessment of Thyroid Function

Thyroid function was assessed during the third visit of the first cohort (RS-I.3) and the first visit of the second (RS-II.1) and third (RS-III.1) cohorts using the same method and assay. Measurements of thyrotropin and FT4 were performed in baseline serum samples stored at −80°C using the ECLIA electrochemiluminescence immunoassay (Roche). The reference ranges of thyrotropin (0.40-4.0 mIU/L) and FT4 (0.86-1.94 ng/dL; to convert to picomoles per liter, multiply by 12.871) were determined on the basis of national guidelines and our previous studies.21,22

Assessment of CVD and Mortality

Outcome measures were incident nonfatal CVD, fatal CVD, and overall mortality. Cardiovascular disease was defined as the presence of coronary heart disease, stroke, or heart failure. Coronary heart disease was defined as coronary revascularization (as a proxy for significant coronary artery disease), fatal or nonfatal myocardial infarction, or fatal coronary heart disease.23 Based on the World Health Organization criteria, stroke was defined as a syndrome of rapidly developing symptoms, with an apparent vascular cause of focal or global cerebral dysfunction lasting 24 hours or longer or leading to death.20,24 Based on the European Society of Cardiology criteria, heart failure was defined as the presence of typical symptoms and signs (ie, breathlessness at rest or during exertion, ankle edema, and pulmonary crepitations), confirmed by the objective evidence of cardiac dysfunction (ie, chest x-ray, echocardiography) or a positive response to the initiated treatment.25 Prevalent CVD was assessed at baseline through interview and medical records. After enrollment, participants were continuously monitored for incident CVD through linkage of the study database with files from general practitioners and hospital records.

Information on mortality was obtained from municipality records, general practitioners, and reports of medical specialists. The underlying cause of death was ascertained independently by 2 research physicians and subsequently validated by a medical specialist.23 In the eMethods in the Supplement, we provide additional information on participants: medical history, medication use, lifestyle, glucose and lipid levels, body mass index, blood pressure, and diabetes mellitus.

Statistical Analysis

Total LE and the number of years lived with and without CVD were calculated among tertiles of thyrotropin and FT4, by using multistate life tables. Differences in LE were evaluated using the lowest tertile as reference. Multistate life tables combined information from participants in 3 possible health states, namely, “free of CVD,” “CVD,” and “death,” Possible transitions of participants were (1) from free of CVD to CVD (incident CVD), (2) from free of CVD to death (mortality among those without CVD), and (3) from CVD to death (mortality among those with CVD). Backflows were not allowed, and only the first event into a state was considered.26 To calculate LE, we followed a similar approach to that of previous studies.27,28

Due to the known sex differences in LE, analyses were performed separately among men and women. We first calculated the prevalence of thyrotropin tertiles among participants with and without CVD, categorized in 10-year age groups. In each transition, we calculated age-specific incidence rates. Next, we applied Poisson regression with Gompertz distribution to compute hazard ratios (HRs) of the association between thyrotropin tertiles and incident CVD or mortality. The confidence intervals of LE estimates were calculated using the Monte Carlo method with 10 000 bootstrap simulations.29(pp184-188) Moreover, we repeated the analyses for the FT4 tertiles.

Analyses were adjusted for potential confounders, which were selected on the basis of biological plausibility and previous literature. Model 1 was adjusted for age and cohort. Model 2 was adjusted for age, cohort, smoking, alcohol intake, education level, marital status, diabetes mellitus, body mass index, systolic blood pressure, total cholesterol, triglycerides, and use of antihypertensive and lipid-lowering medications.

Multiple imputations were performed in case of missing covariates (<5% for all covariates). Statistical analyses were conducted using IBM SPSS, version 21 (IBM Corp); STATA, version 13 for Windows (StataCorp); and @RISK software (Palisade).

Sensitivity Analyses

Several sensitivity analyses were performed: (1) To account for potential reverse causation, we excluded CVD events (n = 179) or deaths (n = 293) that occurred during the first 2 years of follow-up; (2) We excluded participants using thyroid function–altering medications (ie, amiodarone and corticosteroids) (n = 137); (3) To exclude any potential bias caused by presence of cancer at baseline, we additionally adjusted our analyses for prevalent cancer at baseline; (4) To detect a potential influence of follow-up duration on our results, we performed the analyses restricting the length of follow-up to 8 years (median follow-up time).

To additionally explore the association between thyroid status categories (ie, hypothyroidism, euthyroidism, hyperthyroidism) and LE with and without CVD, we extended the study population, including participants of the Rotterdam Study with data available on thyroid function and CVD, without past thyroid disease, and not using thyroid function–altering medications (ie, thyroid medications, amiodarone, or corticosteroids). Participants were categorized on the basis of their thyroid status. Euthyroidism was defined as serum thyrotropin levels within the reference range. Hypothyroidism (clinical and subclinical combined) was defined as high thyrotropin combined with low or normal FT4. Hyperthyroidism (clinical and subclinical combined) was defined as low thyrotropin combined with high or normal FT4. Total LE and LE with and without CVD were calculated in men and women, among thyroid status categories, by using multistate life tables. Differences in LE were evaluated using the euthyroid category as reference.

Results

Baseline characteristics of 7785 eligible participants are presented in Table 1. The mean (SD) age of participants was 64.7 (9.8) years and 52.5% were women. Over a median follow-up time of 8.1 (interquartile range, 2.7-9.9) years, 789 incident CVD events and 1357 deaths occurred. Both models yielded similar estimates; therefore, we further report the results of the most adjusted model (model 2).

Association of Thyroid Function Within the Reference Range With the Risk of CVD and Death

The association of thyrotropin tertiles with the risk of incident CVD was not statistically significant (highest vs lowest thyrotropin tertile: HR, 0.93; 95% CI, 0.79-1.11) (Table 2). Compared with the lowest tertile, the highest thyrotropin tertile was associated with a lower risk of mortality among participants without CVD (HR, 0.76; 95% CI, 0.64-0.91) and with CVD (HR, 0.82; 95% CI, 0.67-1.01) (Table 2).

The highest FT4 tertile was associated with a 1.32 times higher risk of incident CVD than the lowest tertile (95% CI, 1.10-1.58) (Table 2). Compared with the lowest tertile, the highest FT4 tertile was also associated with a 1.64 times higher risk of mortality among participants with CVD (95% CI, 1.32-2.02) and a 1.45 times higher risk of mortality among participants without CVD (95% CI, 1.21-1.73) (Table 2).

Results for thyrotropin and FT4 analyses did not change substantially after the events that occurred during the first 2 years of follow-up were excluded (eTable 1 in the Supplement). Also, results remained similar after excluding users of thyroid function–altering medications and additionally adjusting for the presence of prevalent cancer at baseline (eTable 2 in the Supplement).

Association of Thyroid Function Within the Reference Range With Total LE and LE With and Without CVD

Total LE increased significantly from the lowest to the middle thyrotropin tertile and did not change substantially from the middle to the highest thyrotropin tertile (Figure). Compared with those in the lowest tertile, men in the highest thyrotropin tertile lived 2.0 (95% CI, 1.0 to 2.8) years longer overall, of which, 1.5 (95% CI, 0.2 to 2.6) years longer without CVD and 0.5 (95% CI, −0.5 to 1.4) years longer with CVD (Table 3). Compared with those in the lowest tertile, women in the highest thyrotropin tertile lived 1.4 (95% CI, 0.2 to 2.4) years longer overall, of which, 0.9 (95% CI, −0.2 to 2.0) years longer without CVD and 0.5 (95% CI, −0.5 to 1.2) years longer with CVD (Table 3).

Total LE decreased progressively with increasing FT4 tertiles (Figure). Compared with those in the lowest tertile, the difference in LE for men in the highest FT4 tertile was −3.2 (95% CI, −5.0 to −1.4) years overall, of which, −3.1 (95% CI, −4.9 to −1.4) years without CVD and −0.1 (95% CI, −1.7 to 1.6) years with CVD (Table 3). Compared with those in the lowest tertile, the difference in LE for women in the highest FT4 tertile was −3.5 (95% CI, −5.6 to −1.5) years overall, of which, −2.5 (95% CI, −4.4 to −0.7) years without CVD and −1.0 (95% CI, −2.4 to 0.4) years with CVD (Table 3). Results were consistent over the length of follow-up of 8 years (eTable 3 in the Supplement).

Association of Thyroid Status With Total LE and LE With and Without CVD

Compared with their euthyroid counterparts, hypothyroid men and women lived 0.3 (95% CI, −1.7 to 1.9) and 1.1 (95% CI, −0.4 to 2.3) years longer, respectively (eTable 4 in the Supplement). The difference in LE for hyperthyroid men was −1.4 (95% CI, −4.4 to 2.0) years, compared with euthyroid men. However, these results were not statistically significant. The difference in LE for hyperthyroid women was 2.3 (95% CI, 0.2 to 4.4) years without CVD and −1.9 (95% CI, −3.1 to −0.4) years with CVD, compared with euthyroid women (eTable 4 in the Supplement).

Discussion

In a large prospective population-based cohort study among middle-aged and elderly participants, we investigated differences in LE with and without CVD within the reference range of thyroid function. Participants with low-normal thyroid function lived up to 3.5 years longer overall and up to 3.1 years longer without CVD than participants with high-normal thyroid function. Total LE in euthyroid participants increased from the lowest to the middle thyrotropin tertile but did not change substantially from the middle to the highest thyrotropin tertile. Total LE in euthyroid participants decreased progressively with increasing FT4 tertiles. Overall, there were no meaningful sex differences throughout thyrotropin and FT4 tertiles.

LE without CVD is the resultant of 2 components: risk of incident CVD (transition 1) and risk of mortality among participants without CVD (transition 2). Compared with the lowest tertile, the highest FT4 tertile was associated with a higher risk of incident CVD, meaning an earlier clinical manifestation of CVD and fewer years lived without CVD. The highest FT4 tertile was also associated with an increased mortality risk among participants without CVD, resulting in a further decrease in total LE and LE without CVD. LE with CVD is the resultant of 2 components: risk of incident CVD (transition 1) and risk of mortality among participants with CVD (transition 3). Compared with the lowest tertile, the highest FT4 tertile was associated with a 1.32 times higher risk of incident CVD, meaning an earlier clinical manifestation of CVD and more years lived with CVD. However, participants with CVD in the highest FT4 tertile had an even higher risk of mortality (ie, 1.64 times higher), which explains the decrease in the number of years lived with CVD.

Our study confirms prior research, suggesting that high-normal thyroid function is associated with an increased risk of CVD and mortality, independent of traditional cardiovascular risk factors.2-5 Most importantly, it extends the previous literature by revealing considerable differences in LE within the reference range of thyroid function. These findings provide supporting evidence for a reevaluation of the current reference ranges of thyrotropin and FT4 measurements, implying the possibility of an upward shift of thyrotropin and a downward shift of FT4 reference ranges in middle-aged and elderly people. Further investigations are needed to determine the clinically relevant normal range of thyroid function.

Overactivity of the thyroid gland is known to have a negative effect on overall health. Higher thyroid hormone concentrations have been associated with an increased heart rate (chronotropic effect), myocardial contractility (inotropic effect), and hypercoagulability, which may further predispose to CVD and mortality.6,30 Moreover, elevated thyroid hormone levels can enhance oxygen consumption and production of reactive oxygen species, which may subsequently induce DNA damage and cell apoptosis.31,32 Also, elevated thyroid hormone levels can affect cognition, nerve conduction, and bone mineral density, thus contributing to an increased risk of dementia, polyneuropathy, osteoporosis, and death.33-35 However, the deleterious effects of high thyroid function could also be extended to the high-normal range of thyroid function.2,36 Therefore, the aforementioned mechanisms could be additionally involved in the pathways linking high-normal thyroid function to a reduced life span.

Other mechanisms can explain the association of low-normal thyroid function with a prolonged life span. Low-normal thyroid function may promote energy conservation, which is necessary to adequately cope with acute and chronic stressors.37 Low-normal thyroid function may also represent a heritable phenotype of exceptional longevity. In line with this hypothesis, Rozing et al38 observed lower circulating thyroid hormone levels in middle-aged offspring of nonagenarian siblings compared with age-matched controls. In addition, decreased thyroid hormone levels in nonagenarian siblings have been associated with a prolonged life span in their parents.39

Based on the negative feedback mechanism of the hypothalamus-pituitary-thyroid axis, each individual is expected to have a unique set point of thyroid function, with an inverse relation between thyrotropin and FT4 concentrations. Our results were consistent with the feedback regulation because high-normal thyrotropin levels and low-normal FT4 levels were both associated with an increased LE. However, LE in our participants was more strongly associated with FT4 than with thyrotropin levels. Likewise, previous cohort studies have reported a stronger association of adverse outcomes (including mortality) with FT4 than with thyrotropin levels, particularly within the euthyroid range.2,4,13,14,22,34 Likely, genetic determinants and aging can modify the thyrotropin-FT4 set point of the feedback mechanism among euthyroid individuals.40,41 Various genetic polymorphisms that affect serum thyrotropin but not FT4 levels have been identified.41

In addition, we investigated the differences in LE with and without CVD among thyroid status categories (ie, hypothyroidism, euthyroidism, hyperthyroidism). In line with the results of our main analysis, we found that hypothyroid participants lived longer than euthyroid participants. Among hyperthyroid participants, we observed sex differences in the number of years lived with and without CVD. However, these results should be interpreted with caution, owing to the relatively small number of participants with thyroid dysfunction and their increased susceptibility to receiving treatment and changing health behaviors over time. Future studies can explore more extensively the effect of thyroid disease on LE with and without CVD.

To the best of our knowledge, this is the first population-based cohort study that investigates differences in LE with and without CVD within the reference range of thyroid function. Strengths include the prospective study design, the long follow-up period, and the large number of participants with extensive and detailed information on covariates and outcomes. The large sample size allowed us to conduct multiple sensitivity analyses, which provided consistent findings. Events were adjudicated using standardized criteria.

Limitations

Several limitations should also be considered. The Rotterdam Study includes predominantly whites older than 45 years; therefore, our findings require confirmation in other populations. Moreover, we lacked repeated measurements of thyroid function. Nevertheless, this is unlikely to have affected our results, given that the normal range of thyroid function is considered to be stable over time with a low intra-individual variability.42 Furthermore, we did not have data available on serum triiodothyronine levels. However, thyrotropin and FT4 represent the most relevant measurements of thyroid function in clinical practice. Due to the observational character of our study, the possibility of residual confounding cannot be entirely ruled out.

Conclusions

At the age of 50 years, participants with low-normal thyroid function lived up to 3.5 years longer overall and up to 3.1 years longer without CVD than those with high-normal thyroid function. Our findings support a reevaluation of the current reference ranges of thyrotropin and FT4 measurements, implying the possibility of an upward shift of thyrotropin and a downward shift of FT4 current limits in middle-aged and elderly people. Future research is needed to replicate our findings and elucidate the exact mechanisms underlying the LE differences within the reference range of thyroid function.

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Article Information

Corresponding Author: Robin P. Peeters, MD, PhD, Department of Internal Medicine, Room Ee 502a, Erasmus Medical Center, Dr Molewaterplein 50, Rotterdam 3015 GE, The Netherlands (r.peeters@erasmusmc.nl).

Accepted for Publication: July 21, 2017.

Correction: This article was corrected on November 6, 2017, to fix errors in the second paragraph of the Results and Table 2, footnote a.

Published Online: September 18, 2017. doi:10.1001/jamainternmed.2017.4836

Author Contributions: Drs Peeters and Franco had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Peeters and Franco served as co–senior authors, each with equal contribution to the manuscript.

Study concept and design: Bano, Dhana, Chaker, Mattace-Raso, Peeters, Franco.

Acquisition, analysis, or interpretation of data: Bano, Dhana, Chaker, Kavousi, Ikram, Mattace-Raso, Peeters, Franco.

Drafting of the manuscript: Bano, Chaker, Mattace-Raso, Peeters, Franco.

Critical revision of the manuscript for important intellectual content: Bano, Dhana, Chaker, Kavousi, Ikram, Mattace-Raso, Peeters, Franco.

Statistical analysis: Bano, Dhana, Chaker, Franco.

Obtained funding: Ikram, Peeters, Franco.

Administrative, technical, or material support: Chaker, Kavousi, Peeters, Franco.

Supervision: Chaker, Ikram, Mattace-Raso, Peeters, Franco.

Conflict of Interest Disclosures: Dr Peeters has received lecture fees from IBSA and Goodlife Fertility. Dr Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd) and Metagenics Inc. No other disclosures are reported.

Funding/Support: Drs Chaker and Peeters are supported by the Netherlands Organization for Health Research and Development Zon-MWTOP grant 91212044 and an Erasmus Medical Center Medical Research Advisory Committee grant. Dr Kavousi is supported by a VENI grant from the Netherlands Organization for Scientific Research (VENI 91616079). The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Netherlands Genomics Initiative; the Netherlands Ministry of Education, Culture and Science; the Netherlands Ministry of Health Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam.

Role of the Funder/Sponsor: The funding sources 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; and decision to submit the manuscript for publication.

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