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Volume 12 No. 06
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Accepted Papers





Scientific Investigations

http://dx.doi.org/10.5664/jcsm.5870

Nocturia, Insomnia Symptoms and Mortality among Older Men: The Health, Aging and Body Composition Study

Yohannes W. Endeshaw, MD, MPH1; Ann V. Schwartz, PhD, MPH2; Katie Stone, PhD3; Paolo Caserotti, PhD4; Tamara Harris, MD, MS5; Stephen Smagula, PhD6; Suzanne Satterfield, MD, DrPH7
1Geriatrics Section, Department of Medicine, Morehouse School of Medicine, Atlanta GA; 2Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco CA; 3Research Institute, California Pacific Medical Center, San Francisco, CA; 4University of Southern Denmark-Institute of Sports Science and Clinical Biomechanics, Odense, Denmark; 5Intramural Research Program, Laboratory of Epidemiology and Population Science, National Institute on Aging, Bethesda, MD; 6Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA; 7Department of Preventive Medicine, University of Tennessee, Health Science Center, Memphis, TN

ABSTRACT

Study Objectives:

To examine the association between nocturia (walking up from sleep for urination) and mortality risk among community dwelling older men.

Methods:

This is a secondary data analysis using data obtained from the Health Aging Body Composition (Health ABC) study. Frequency of nocturia was determined at baseline using a questionnaire.

Results:

A total of 1,478 older men, mean (SD) age 73.8 (2.9) years, were included in the analysis. During a follow up period of 9.9 years, a total of 760 deaths were reported. Mortality rate was significantly higher for participants with 3 or more nocturia episodes per night, in comparison to those with 0–1 episodes (HR [CI] : 1.21 [1.00–1.47], p = 0.055), even after controlling for baseline characteristics which included demographic variables, body mass index, lower urinary tract symptoms, use of loop diuretics, insomnia symptoms, feeling excessively sleepy during the day/daytime naps, sleep duration, and use of sleep medications. However, the association between ≥ 3 nocturia episodes per night and mortality risk was no longer statistically significant once prevalent diabetes mellitus and cardiovascular disease were included in the model (HR [CI]: 1.18 [0.97- 1.44], p = 0.100).

Conclusions:

Nocturia is associated with mortality independent of insomnia symptoms and sleep duration. The relationship is explained in part by prevalent cardiovascular disease and diabetes mellitus. The results underscore the impact of these medical conditions on the association between 3 or more nocturia episodes and increased mortality risk among older men.

Citation:

Endeshaw YW, Schwartz AV, Stone K, Caserotti P, Harris T, Smagula S, Satterfield S, Health ABC Study. Nocturia, insomnia symptoms and mortality among older men: the health, aging and body composition study. J Clin Sleep Med 2016;12(6):789–796.


INTRODUCTION

Nocturia, commonly known as one of the lower urinary tract symptoms (LUTS), is also a common sleep related complaint among older adults,1–5 with two or more nocturia episodes per night reported by over 30% of the elderly.6–9 Multiple factors contribute to the high prevalence of nocturia among older men. Age related changes in the genitourinary system such as decreased bladder capacity and benign prostatic hypertrophy increase the risk of frequent urination.6,7,10–13 Other factors implicated in the pathogenesis of nocturia include polyuria and/or nocturnal polyuria which could be due to uncontrolled diabetes mellitus, vasopressin deficiency, fluid redistribution in supine position associated with edematous states such as congestive heart failure, low albumin, chronic kidney disease, as well as primary sleep disorders such as obstructive sleep apnea and hypopnea.14–18 In some cases, individuals may report the need to urinate as the reason for their waking up from sleep, even if they wake up for reasons unrelated to bladder pathology.3

BRIEF SUMMARY

Current Knowledge/Study Rationale: Nocturia is a common complaint among older adults and associated with sleep related complaints, as well as higher morbidity burden and mortality rate. In this study, we examine if the association between nocturia and mortality is independent of insomnia symptoms, prevalent diabetes mellitus and cardiovascular morbidity.

Study Impact: Results of the study indicate that the association between 3 or more nocturia episodes and mortality is independent of insomnia symptoms and this association may be partly explained by prevalent diabetes mellitus and cardiovascular morbidity. These findings underscore the importance of these morbidities on the association between frequent nocturia episodes and higher mortality rate.

As previously suggested,19 the cause of nocturia among older men is most probably multifactorial, and this could explain the previously reported associations between frequent nocturia episodes and higher disease burden.20,21 Additionally, previous studies have reported significant association between frequent nocturia episodes and higher mortality risk among older adults with cardiovascular disease and diabetes mellitus.22,23 Furthermore, nocturia has been reported to predict mortality risk among older adults even after controlling for diabetes mellitus and cardiovascular disease.24,25 One of the mechanisms that is forwarded to explain the association between nocturia and higher mortality risk is sleep disturbance caused by nocturia episodes.25 However, we are not aware of any published studies that examined if the association between nocturia and mortality risk is independent of sleep disturbance. The first objective of the current study is to examine whether nocturia predicts higher mortality risk independent of sleep related factors such as insomnia symptoms, sleep duration, and use of sleep medications.

Two of the common causes of nocturia, cardiovascular disease and diabetes mellitus, are also leading causes of death among older adults,26 suggesting that these medical conditions could explain the association between nocturia frequency and mortality risk. However, two previous studies have reported significant associations between nocturia and higher mortality risk even after controlling for cardiovascular disease and diabetes mellitus, although these studies have several limitations. For example, in one of the studies, participants were mostly white older men and women living in Sweden,24 and whether findings from this study would be applicable to older men of other racial groups may be debatable. In both of these studies,24,25 prevalent cardiovascular disease and diabetes mellitus were determined based on single questions for each of these conditions, and these questions may not capture the full spectrum of these medical conditions. The second objective of the current study is to examine whether the association between nocturia frequency and mortality is independent of cardiovascular disease and diabetes mellitus, using well-characterized data derived from a biracial sample of older men.

METHODS

Study Population

De-identified data for the current analysis are obtained from the Health Aging and Body Composition (Health ABC) study. Details about recruitment in Health ABC study have been described previously.27 In short, this is a prospective cohort study in which 3,075 (1,584 females and 1,491 males) community dwelling older adults between the age of 70 to 79 years and living in areas surrounding Pittsburgh, PA, and Memphis, TN, were recruited between March 1997 and July 1998. Because information on nocturia was not collected from women in the Health ABC study, the current analysis was performed based on data obtained from male participants (n = 1,491).

Nocturia Frequency

The International Prostate Symptoms Score (I-PSS) questionnaire, administered at baseline, includes the following question: “During the past 30 days, how many times did you most typically get up to urinate from the time you went to bed at night until the time you got up in the morning?” Response choices to the nocturia question included “0,” “1,” “2,” “3,” “4,” and “5 or more.” In the current analysis, study participants were categorized into 3 groups based on self-reported nocturia frequency ”0 to 1,” “2,” or “3 or more” times per night. Lower urinary tract symptom score was derived from participant's response to the I-PSS questionnaire after excluding response to the nocturia question. Of a total of 1,491 male participants, data on nocturia was available for 1,478 participants (99%) (13 participants, 10 white and 3 black, did not complete the I-PSS questionnaire).

Sleep Assessment

Insomnia symptoms were determined based on responses to the following questions. How often do you experience the following: (1) “trouble falling asleep,” (2) “waking up from sleep with difficulty going back to sleep,” (3) “waking up too early in the morning and be unable to go back to sleep,” and (4) “feeling not rested during the day no matter how many hour of sleep you had.” Responses to these questions included “Never,” “Rarely,” “Sometimes,” “Often,” and “Almost Always”; participants who responded “Often” or “Almost Always” to any one of the questions were considered to have significant insomnia symptoms. Based on this definition, 3 categories were created, including: (1) participants with none of these insomnia symptoms; (2) participants with difficulty falling asleep, staying asleep, or waking up too early in the morning, but no symptoms related to feeling not rested during the day; and (3) participants who reported insomnia symptoms as above and feeling not rested during the day. In addition, daytime sleep-wake related complaints were assessed based on response to the following 2 questions: (1) “How often do you feel excessively (overly) sleepy during the day (excessively sleepy)?” and response to this question included “never,” “rarely,” “sometimes,” “often,” and always”; (2) “During a usual week, how many times do you nap for 5 minutes or more (daytime nap)?” and responses were recorded as the number of naps per week. For the purpose of this analysis, “excessively sleepy” and “daytime nap” were combined (sleepiness/napping) and 2 categories were created as follows: (1): Excessively sleepy (never, rarely, sometimes) or naps (0 or 1–7 per week); and (2): Excessively sleepy (often, always) or naps (> 7 per week).

Self-reported sleep duration was assessed using the following question “How many hours of sleep do you usually get at night?” Participants responded with duration of sleep in hours. Use of sleep medication was determined based on the question “Do you take sleeping pills or other medication to help you sleep” with the following responses: “Never,” “Rarely,” “Sometimes,” “Often,” or “Almost Always.”

Follow-up

After initial clinic visit for baseline evaluation, participants were requested to return to clinic at 12 months for follow-up assessment. In addition, telephone interview assessments were done 6 months after baseline and yearly clinic-visit assessments. Study participants or individuals who were identified as proxy were contacted (if the participant could not be reached) during these follow-up visits and telephone interviews. Deaths were identified during 6-month telephone interviews, during scheduling for annual clinic visits, or by review of obituaries. Once death of a participant was reported, “Decedent Proxy Interview” of a designated proxy or next of kin was conducted by study personnel, and death certificates and relevant medical records were obtained for adjudication of cause of death.28 Deaths included in this analysis were ascertained through March 2011. Vital status (alive or died) was available for 1,424 participants (96%), and participants for whom information on vital status was not available were assumed to be alive. Documented date of last contact was taken as the censor date for those who were alive and those on whom vital status information was not available.

Baseline Characteristics

Baseline variables of interest included demographic variables as well as clinical variables that have been previously associated with nocturia and/or sleep disturbance. These included body mass index (BMI), smoking status, alcohol consumption, lower urinary tract symptoms, history of cardiovascular disease, and diabetes mellitus. Weight and height were measured at baseline and BMI was calculated based on the standard formula (weight in kilograms divided by height in meters squared). Prevalent cardiovascular disease at baseline was determined based on the following criteria: (1) History of coronary artery bypass graft surgery, or (2) history of carotid endarterectomy, or (3) self-reported history of myocardial infarction and use of anti-angina medication, or (4) major Q-wave abnormality on baseline electrocardiogram, or (5) history of congestive heart failure. Prevalent diabetes mellitus (DM) was determined based on self-reported history or use of medication for DM or fasting blood sugar of > 126 mg/dL at baseline. Responses to the following 2 questions were used to determine history of falls. “During the past 12 months, have you fallen and landed on the ground?” and “How many times have you fallen in the last 12 months?” History of fracture was derived from response to the following question: “Has a doctor ever told you that you broke or fractured a bone after the age of 45?”

Statistical Analysis

Baseline Characteristics

Demographic and clinical characteristics of participants by frequency of nocturia status were determined using one-way analysis of variance and χ2 test statistics for continuous and categorical variables, respectively. Linear trend across nocturia groups was determined using a modified Wilcoxon rank test available in Stata statistical software.29

Mortality

Time interval between last date of contact or date of death and date of first clinic visit (time 0) was utilized to calculate participant follow-up time. Kaplan-Meier survival curves were used to plot pattern of survival time by frequency of nocturia. Cox proportional hazards (PH) and Cox time dependent covariate models were used to evaluate the association between nocturia frequency and mortality.

Demographic and baseline clinical characteristics were considered for inclusion in the Cox PH model if they had previously been associated with nocturia and/or mortality, or if they were deemed biologically relevant. These covariates were: age, race, study site, education level, marital status, baseline BMI, smoking status, use of alcoholic drinks, I-PSS score (excluding nocturia), use of loop diuretics, insomnia symptoms, sleep duration, use of sleep medications, daytime sleepiness/ nap behavior, prevalent cardiovascular disease, and prevalent diabetes mellitus.

To determine whether these variables should be included in the model, Kaplan-Meier survival curve for each of the categorical covariates and Cox-regression model for each of the continuous variables were run separately with mortality as the outcome of interest. Variables that were associated with mortality at p value ≤ 0.05 were included in the final Cox regression model. Interaction terms that include nocturia frequency and age, race, study site, insomnia complaints, use of sleep aids, and body mass index were also included in the model.

A total of 4 Cox-regression models were created, including: Model 1 unadjusted model; model 2 which included model 1 and demographic and lifestyle related variables; model 3 which included variables in model 2 and BMI, lower urinary tract symptoms, use of loop diuretics, insomnia symptoms, sleepiness/napping, sleep duration, and use of sleep medication; and model 4 which include variables in model 3 and prevalent diabetes mellitus and cardiovascular disease. Because there was no significant relationship between nocturia episodes and history of falls/fractures, they were not included in the regression model. In order to exclude the possible effect of use of sleep medications on the association between nocturia status and risk of mortality, Cox regression analysis was repeated after excluding participants who reported use of sleep aids. A two-sided p value < 0.05 was used to indicate statistical significance. Analyses were performed using Stata version 13 software.

RESULTS

Nocturia Frequency

A total of 1,478 participants responded to the nocturia question and are included in the analysis. Nocturia episodes per night were reported as 0, 1, 2, and 3 or more by 12%, 39%, 26%, and 23% of participants, respectively. Table 1 and Table 2 show selected demographic and clinical characteristics of study participants by nocturia frequency. Three or more and two episodes of nocturia were more prevalent among black participants than white participants (26% vs. 20% for ≥ 3 nocturia episodes and 28% vs. 26% for 2 nocturia episodes, respectively, p = 0.005). However, after stratification by educational status, significant difference in nocturia frequency between black and white study participants was observed only among participants with less than 12 years of education (29% vs. 15% for ≥ 3 nocturia episodes, and 28% vs. 24% for 2 nocturia episodes [p = 0.015], respectively). As expected, the prevalence of cardiovascular disease and diabetes mellitus were higher among participants with higher nocturia frequency. At baseline, a total of 271 participants (19%) reported one or more falls, with 185 participants (13%) reporting a single fall, while 86 participants (6%) reported two or more falls; and there was no significant association between nocturia frequency and falls. A total of 238 participants (16%) reported fracture (any bone), while 11 participants (< 1%) reported hip fracture during the previous 12 months; and there was no significant association between nocturia episodes and history of fracture.

Selected demographic and lifestyle characteristics of study participants by nocturia frequency at baseline.

jcsm.12.6.789.t01.jpg

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Table 1

Selected demographic and lifestyle characteristics of study participants by nocturia frequency at baseline.

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Selected clinical characteristics of study participants by nocturia frequency at baseline.

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Table 2

Selected clinical characteristics of study participants by nocturia frequency at baseline.

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Table 3 shows the distribution of sleep related complaints among study participants by nocturia status. As shown, the proportion of participants who reported insomnia symptoms was higher among those with increased frequency of nocturia episodes. Overall, 19%, 25%, and 33% of participants with 0–1, 2, and ≥ 3 nocturia episodes, respectively, reported one or more insomnia symptoms (p < 0.001). Participants with ≥ 3 nocturia episodes were also more likely to report feeling excessively sleepy during the day often or always (p < 0.001), and taking more than 7 naps per week (p = 0.005). There was no statistically significant relationship between nocturia symptoms and sleep duration.

Baseline sleep characteristics of study participants by nocturia frequency.

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Table 3

Baseline sleep characteristics of study participants by nocturia frequency.

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A total of 760 of 1,478 participants (51%) died during the study period. Mortality rates were higher for participants who reported ≥ 3 nocturia episodes, compared with those who reported 2 and 0–1 nocturia episodes per night (83 per 1,000 PY, 63 per 1,000 PY, and 59 per 1,000 PY respectively). Cardiovascular diseases and diabetes mellitus accounted for 37% and 1% of the underlying causes of death, while malignant neoplasm and dementia were reported as underlying causes of death in 30% and 8% of study participants, respectively. Of the malignant neoplasms reported as underlying causes of death, lung cancer, prostate cancer, and colon cancer accounted for 25%, 13%, and 10% of the cancers. Figure 1 shows Kaplan Meier survival curves by nocturia frequency, and as shown participants with ≥ 3 nocturia episodes had significantly lower survival rates during follow-up.

Kaplan-Meier survival estimates by nocturia frequency.

Log rank test p = 0.007.

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Figure 1

Kaplan-Meier survival estimates by nocturia frequency.

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Table 4 shows mortality hazard rates by nocturia frequency in unadjusted and adjusted Cox regression models. As shown, hazard rate was significantly elevated among participants with ≥ 3 nocturia episodes compared with those with 2 and 0–1 nocturia episodes per night, even after adjusting for potentially confounding factors which include demographic and lifestyle variables, BMI, lower urinary tract symptoms, insomnia symptoms, sleep duration, use of sleep medications and sleepy/napping (HR [CI]: 1.21 [1.00–1.47], p = 0.055). There were no significant interactions between nocturia frequency and age, race, study site, insomnia symptoms, sleep medication use, and BMI (p > 0.1).

Results of Cox proportional hazard models showing the association between nocturia frequency and mortality (outcome variable) in unadjusted and adjusted models.

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Table 4

Results of Cox proportional hazard models showing the association between nocturia frequency and mortality (outcome variable) in unadjusted and adjusted models.

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Results of Cox regression analysis performed after including prevalent cardiovascular disease and diabetes mellitus (Table 4, Model 4) showed that there was no longer statistically significant association between three or more nocturia episodes and risk of mortality (HR [CI]: 1.18 [0.97–1.44], p = 0.100). Cox regression analysis after excluding participants who reported taking sleep medications did not change the association between nocturia status and risk of mortality. Analysis was also repeated with 2 nocturia categories (0–1 episodes and ≥ 2 episodes per night), and there was no statistically significant difference in hazard rate for mortality between the 2 groups.

Proportional-hazard (PH) assumption using Schoenfeld residuals showed global test p value of = 0.016, and PH assumption was violated for the following variables: smoking (p = 0.03), body mass index (p = 0.012), and use of loop diuretics (p = 0.004). For this reason, Cox regression analysis with time-varying covariates was performed, and this result is reported in Table 4, model 4.

A total of 145 participants had missing values for one or more covariates and were not included in the Cox regression model 4. Those with missing values were older (74.1 vs. 73.7 years, p = 0.007), and more participants were from Pittsburgh study site than the Memphis site (15.8% vs. 12.2%, p = 0.04). Otherwise, there were no significant differences between participants who were and were not included in the final model in other characteristics, including race, smoking and drinking status, body mass index, insomnia symptoms, sleep duration, I-PSS score, morbidity burden, physical performance score, or nocturia frequency.

DISCUSSION

Results of the current study indicate significant association between 3 or more nocturia episodes per night and increased mortality rate during follow-up among community dwelling older men. This association was statistically significant even after controlling for demographic characteristics, smoking and alcohol use history, BMI, lower urinary tract symptoms, use of loop diuretics, as well as sleep related factors which include insomnia symptoms, feeling excessively sleepy during the day/daytime naps, sleep duration and use of sleep medications. These findings suggest that the association between nocturia and higher mortality risk is independent of sleep-related factors included in this study, and to our knowledge, this is the first study to report such results. However, the association between nocturia and mortality risk was attenuated and was not statistically significant when prevalent cardiovascular disease and prevalent diabetes mellitus were included in the model, suggesting that the association between nocturia and mortality risk could be explained at least in part by these two medical conditions.

Our result is in contrast to at least two previous studies mentioned above that reported significant association between nocturia and mortality risk even after controlling for prevalent diabetes and cardiovascular disease.24,25 Several factors can account for the different findings in the current study and those reported previously. In one of these studies, study participants included older men and women living in Sweden,24 and in the current study participants were comprised of a biracial sample of older men. Furthermore, in both studies quoted above, prevalent cardiovascular disease and diabetes mellitus were determined based on the response to a single question for each of these medical conditions; while in the current study, multiple questions as well as objective data were used to ascertain prevalent cardiovascular disease and diabetes mellitus. Last but not least, unlike the aforementioned studies, sleep-related factors and lower urinary tract symptoms were included as covariates in the current study. We think that these factors could account for the difference in the results.

The findings in our study are also in contrast to a recent study which failed to show significant association between nocturia frequency and risk of mortality after controlling for age of participants.30 In this recent study, the participants were younger with a median age of 60.8 years (Q1-Q3, 56.0–66.2 years), in comparison to our study in which the median age was 74.0 years (Q1-Q3, 71.0–76 years). In addition, this recent study used frequency volume chart (FVC) to estimate nocturia frequency, whereas in our study, nocturia frequency was self-reported. In the current study, information on the number of times the person wakes up from sleep for urination during the previous 30 days is obtained using a questionnaire, while the FVC estimates number of nocturia episodes over the last few days. It has been previously reported that there is only a modest correlation between questionnaire based nocturia episodes and FVC derived nocturia frequency,31 suggesting that these two methods may be measuring different dimensions of nocturia. Furthermore, the study that reported nocturia frequency based on FVC excluded participants with history of prostatectomy, prostate cancer, bladder cancer, neurogenic bladder, while there was no exclusion made based on these diagnoses in our study. We think that these factors could explain at least in part the differences in the results between our study and the recent study mentioned above.

There was significant association between nocturia frequency and insomnia symptoms with the association showing a possible dose-response relationship, and this finding is in agreement with previous reports.4,32 However, we did not find a significant association between nocturia frequency and sleep duration, and this is in contrast to a previous study that reported longer sleep duration among participants with higher nocturia frequency.8

In contrast to previous studies that reported significant association between nocturia frequency and prevalent as well as incident falls,33,34 no significant association was observed in the current study. Several factors may account for this discrepancy. One factor may be the definition of falls used in these studies. In the current study, participants were asked if they had fallen down during the last 12 months, and recalling of events that happened during the last 12 months may vary among study participants. Furthermore, the current study included older men only, while previous studies that reported association between nocturia episodes and falls included both men and women.

Similar to reports from previous studies,8,35,36 prevalence of nocturia was significantly higher among black older men than white older men (Table 1); however, after stratification of participants by education status, the relationship between nocturia and race was only significant among those with lower education level (< 12 years of education). Further research would be needed to clarify whether socioeconomic related factors explain the association between race and nocturia frequency found in the current study.

Our study has several strengths. Participants are older men living independently in the community at recruitment, and their medical problems were well characterized at baseline. In addition, regular follow-up of study participants was done during the study period. However, the current study also has limitations, which should be taken in to consideration when interpreting the results. Nocturia status was determined only once at baseline, and data on whether nocturia frequency has changed over time is not known. At least one previous study has indicated that the occurrence of nocturia may fluctuate with time, although this fluctuation was more common among middle-aged adults than among older adults.37 Another limitation may be related to insomnia categories used in the current study. Insomnia was ascertained based on self-reported symptoms and no objective sleep measures were used. It is possible that some of the participants with insomnia related complaints could have additional primary sleep disorders that could account for their symptoms.

In conclusion, results of the current study indicate that nocturia is associated with mortality independent of insomnia symptoms and sleep duration. This association may be explained by prevalent cardiovascular disease and diabetes mellitus. The results underscore the impact of these medical conditions on the association between nocturia and mortality risk among older men.

DISCLOSURE STATEMENT

This was not an industry supported study. This research was supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050, P30-AG-31054 and NINR grant R01-NR012459. This research was also supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Dr. Stone has consulted for Merck. The other authors have indicated no financial conflict of interest.

ABBREVIATIONS

BMI

body mass index

CI

confidence Interval

FVC

frequency volume chart

Health ABC study

Health Aging Body Composition study

HR

hazard ratio

I-PSS questionnaire

International Prostate Symptoms Score questionnaire

LUTS

lower urinary tract symptoms

PH

proportional hazards

Q1

first quartile

Q3

third quartile

SD

standard deviation

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