Incidence, worsening and risk factors of daytime sleepiness in a population-based 5-year longitudinal study

Excessive daytime sleepiness (EDS) is highly prevalent in the general population; however little is known about its evolution and predictors. Our objectives were to document its natural history, provide estimates of its prevalence, incidence and persistence rates, and to identify predictors of increased daytime sleepiness (DS) in a longitudinal community study of 2157 adults over 5 years. Participants completed postal assessment at baseline and at each yearly follow-up. DS was evaluated by the Epworth Sleepiness scale (ESS). At baseline, 33% reported EDS (ESS > 10) with 33% of them reported persistent EDS. Of those without EDS at baseline, 28% developed incident EDS (15% were persistent) and 31% increased DS (augmentation ≥4-points between two consecutive evaluations). Younger age and depression were independent predictors of incident EDS and DS increase while lower coffee consumption, smoking, insomnia, tiredness and chronic pain were associated with incident EDS, and living alone with DS increase only. Persistent vs transient EDS or DS showed association with poor general health including metabolic diseases. Thus, sleepiness fluctuated over time and it was predicted by common lifestyle and psychological factors potentially modifiable. However, persistent sleepiness was associated with chronic medical diseases thus highlighting a homogeneous group at risk requiring a dedicated management.

. However, trajectories of EDS vary considerably with approximately 8% of new cases each year, between 8 and 13% of remitted cases since the previous year and approximately 19% of recurrent cases since the previous year (Fig. 2). Regarding the persistence of EDS during the follow-up, 32.6% (n = 233) reported a persistent EDS at baseline and at all 5 subsequent assessments, 25 developed EDS after 1-year of follow-up with a persistence at all subsequent assessments, 14 after two years, 13 after three years and 11 after four years.
Determinants of EDS at baseline. Participants with EDS were younger, slept less than eight hours per night, had a higher frequency of naps, and took hypnotics less frequently (Table 1). They were more likely to complain insomnia, fatigue, depressive and anxiety symptoms, were obese and less physically active, and reported higher rates of diagnoses of sleep apnea, chronic pain, neurological or other diseases (p ≤ 0.02 for all comparisons) ( Table 1). To identify which determinants were independently associated with EDS, gender and other characteristics associated with EDS at p < 0.15 were introduced into a multivariate model. Younger age, shorter sleep duration, higher frequency of naps, fatigue, levels of trait-anxiety, sleep apnea and the absence of hypnotic consumption were associated with EDS, but not insomnia, depressive symptoms or chronic diseases (Table 1).
To examine whether determinants could be differentially associated with EDS severity, subjects were categorized into three groups: no EDS (ESS ≤ 10, n = 1453), EDS (ESS between 11 and 15, n = 533) and severe EDS Scientific RepoRts | 7: 1372 | DOI: 10.1038/s41598-017-01547-0 (ESS ≥ 16, n = 181). Compared to those without EDS, those with EDS or severe EDS were independently more tired, trait-anxious, had frequent naps and consumed no hypnotic whereas those with non-severe EDS only were younger and reported more short sleep duration, and those with severe EDS only had more sleep apnea.

Predictors of EDS over 5-year follow-up.
Among the 1453 subjects without EDS at baseline, 411 (28.3%) met criteria for incident EDS at least in one of the subsequent follow-ups. The median occurrence of the first EDS event was 2 years [range of 0.40-5.71].
In bivariate Cox models including time-dependent variables, the risk of incident EDS was higher in subjects living alone, smoking occasionally, consuming less coffee, sleeping less than eight hours, taking frequently naps, practicing physical activities less than 4 times per week, being insomniac, tired and depressed, less anxious, and with chronic diseases (restless legs syndrome, chronic pain, endocrine, metabolic neurological and other diseases) ( Table 2). BMI category or a change in BMI categories was not significantly associated with incident EDS. In a Cox multivariate model including gender, ESS baseline and characteristics associated with a p < 0.15, being younger (borderline significant), consuming less coffee, smoking occasionally, being insomniac, depressed, with fatigue and having chronic pain were independent predictors of the incidence of EDS (Table 3). To test whether a potential multicollinearity of fatigue, depression symptoms and insomnia, several multivariate models were rerun including all covariates associated at p < 0.15 1) without the covariate fatigue 2) without the depression symptoms 3) without insomnia severity. The results of associations between potential predictors and incidence of EDS during the 5-year follow-up remained unchanged.
Among the participants with incident EDS, only 15.3% (n = 63) reported a persistent EDS in all subsequent assessments. Compared to participants with transient EDS, participants with persistent EDS reported a higher frequency of diabetes (HR = 3.23 95% CI = [1.51;6.91], p = 0.003) in bivariate analysis and this result remained unchanged after adjustment for gender, age and ESS baseline (HR = 3.10 95% CI = [1.40;6.85], p = 0.005).

Predictors of increased DS over 5-year follow-up.
Over the 5-year follow-up, 658 (31.3%) participants had increased DS (≥4 points on ESS) with a median delay between baseline and follow-up augmentation of 2.16 years [range of 0. 25-5.59].
In bivariate Cox models including time-dependent variables, participants with increased DS were significantly more likely to have a low educational level, live alone, sleep less than eight hours per night, practice physical activities less than 4 hours per week and reported more severe insomnia, fatigue, and depressive symptoms. They were more obese and reported more chronic diseases (chronic pain, diabetes, cardiovascular, endocrine and metabolic, neurological and other diseases) ( Table 2). In a multivariate model, participants with increased DS were independently younger, lived alone and more depressed (

Discussion
In this study of community-dwelling middle aged adults, 33% of the participants met the criteria for self-reported EDS at baseline (ESS > 10) (of whom 25% had severe EDS), with 33% of them reporting persistent EDS over 5 years. During the follow-up, 28% had incident EDS and 31% had increased DS (≥4-point on ESS). However, the course of EDS fluctuates over time with only 15% having persistent EDS and 36% persistent DS. We found that  Continued younger age and depressive symptoms were independent predictors of incident EDS and DS increase while lower coffee consumption, smoking, insomnia, tiredness and chronic pain were associated with incident EDS, and living alone with DS increase only. Only poor general health with somatic diseases, especially metabolic diseases, was associated with persistent EDS or DS increased. We evaluated DS using the ESS which is based more on observable behaviors than subjective experience, reflecting real-life experience, with a good correlation found between the scores obtained by patients and their partners. The score is reliable and reproducible with good test-retest reliability (r = 0.82) between two administrations of the ESS over a time period of 5-months 22 . Prevalence rates for EDS were in the same range at baseline and at each point of the follow-up. These estimations were, however, higher than previous studies using the same questionnaire, ranging from 8.5 to 22.2% 5,8,11,15,16 . Reasons for such estimations may be due to the administration mode of the ESS scale, being here self-reported and completed via a postal mailing thus without clear face-to-face information on how to answer it. It has been reported higher score when the questionnaire was only self-administrated 23 . Consequently, we cannot excluded a certain degree of misclassification, with some overlapping with fatigue.
In our study, no gender difference was found while EDS slightly decreased with age as previously reported 8,15 . In contrast, shorter sleep duration, higher frequency of naps, fatigue, higher levels of trait-anxiety and the absence of hypnotic consumption were associated with EDS. Only sleep apnea was related to severe EDS (ESS > 16).
We also found a high frequency of incident EDS (28%) over the 5-year period compared to previous studies 8, 15 . However, among participants who developed EDS in our study only 15% were persistent which suggests instability, with frequent waxing and waning in the natural course of EDS in the general population. This finding could not be assessed in previous studies, as no data on DS were available between baseline and endpoint follow-up 8,15 . Low persistent EDS rate was, however, in agreement with a recent study measuring EDS using two single questions 21 . Among participants with EDS at baseline, 21% only persisted at the 10-year follow-up 21 . Thus, EDS appears to be an unstable symptom in the general population and cannot be considered as a disorder per se 24 .
In addition to changes in the trajectory of sleepiness propensity with time, we investigated the test-retest reliability of the tool. Despite its widespread use, and its good psychometric properties in students 22 , a systematic review of the ESS showed poor test-retest reliability especially in middle-aged populations and after a time period greater than one year 25 . Furthermore, despite validated norms in healthy subjects with scores between 0 and 10, a grey zone for pathological scores existed with doubt for some conditions due to potential difficulties in understanding the questions and the quality of the subject's perception of their sleepiness. Moreover, significant changes within the scores may occur even under the threshold (i.e. the "presymptomatic stage"), or already above the threshold referring to an aggravation of the condition. Accordingly, we reanalyzed the ESS scores when there was an increase of 4-points or more between two consecutive evaluations. As already reported in the literature 17,18 such an important difference in DS may be considered as clinically meaningful and should therefore alert the clinician. Results showed that 33% had increased DS but only 36% were persistent; although this is low, it is twice as high as for persistent EDS.
Other important findings of our study concerned the risk factors associated with incident EDS and DS increase. We found that younger age was an independent predictor of incident EDS and DS increase but did not observe a U-shaped relationship as previously described for EDS 21 . We replicated the association between depressive symptoms and incident EDS and DS increase shown in others studies 20,21 . We also reported that lifestyle factors (i.e. lower coffee consumption and smoking) were associated with incident EDS and living alone with  20 . These two lifestyle factors were related to EDS with mechanisms of action being potentially related to the stimulant effect of caffeine and the non-restorative sleep effect of nicotine 26 . In the same way, insomnia, fatigue and chronic pain, being markers of poor health status, were associated with incident EDS. Fatigue and insomnia were already reported as potential risk factors for EDS but to our knowledge we reported for the first time that chronic pain may be a risk factor for EDS in the general population. The mechanism underlying this association remains unknown but it may involve sleep fragmentation and chronic low-grade inflammation 27,28 . Several arguments already suggest a complex relationship between insomnia, hypersomnia and chronic pain 29 . We failed to report any relationship between change of BMI classes and EDS/DS onset. This discrepancy may relate to the low proportions of subjects with obesity (~20%) and with significant BMI changes in our sample (~15%). Last, typical short sleep duration was associated with incidence of EDS and DS increase in bivariate models with similar tendency for the former outcome in multivariate model. Finally, potential association with long sleep duration defined as >9 hours in the literature 30 could not be assessed here as it corresponds to only 6% (n = 88) of the population. We also identify predictors of persistent vs transient EDS or DS increase that showed associations with poor general health including somatic diseases and especially metabolic diseases. None of lifestyle and psychological factors were associated with persistent sleepiness. Findings focusing on subjects with persistent sleepiness are of major interest as they highlight a more homogeneous group potentially at risk for serious medical consequences such as cardiovascular and neurodegenerative disorders. Interventional studies exploring whether the management of sleep complaint improves or prevents the medical condition, and whether the management of the medical condition improves sleep symptoms, are warranted in these subjects with persistent sleepiness.
The strengths of this present study are the prospective design, the size of the cohort and the large number of potential risk factors including socio-demographic, lifestyle, health and psychological variables. The study had also a long follow-up of five years with yearly evaluations allowing assessment of potential fluctuation of sleepiness course and changes in covariates over time. Furthermore, the evaluation of EDS was assessed using the ESS which is the most commonly used tool in sleep research and clinical setting.
This study has some limitations. Selection bias may exist even if random selection was used for the recruitment of the participants. The data are self-reported with possible recall and common method bias. The responses when filling the questionnaire may depend on the participant's perceptual experience. Objective measures of sleep quality and DS by polysomnographic (PSG) and multiple sleep latency test (MSLT) recordings were not available for this study; however, performing PSG and MSLT were very difficult within the context of a large epidemiological survey. Moreover the agreement between objective and subjective EDS was always unsatisfactory.
In conclusion, our study reports a high fluctuation of EDS and increased DS over time in the general population. Sleepiness is predicted by a similar set of lifestyle and psychological factors that are potentially modifiable.  Table 2. Predictors of incident excessive daytime sleepiness (EDS) and daytime sleepiness (DS) increased over of 5-year follow-up. (1) Change between the two last evaluations before the 4-point increase.

Methods
Study population. Subjects included were recruited as part of a larger epidemiological study aiming to assess prevalence and incidence, risk factors, natural history, and burden of insomnia in Canada. Detailed design and sampling procedures for this study have been reported elsewhere 31 . Briefly, subjects aged ≥18 years were recruited from a random selection of more than 12000 subjects who completed a telephone interview about their sleep between 2007 and 2008. Participants were then asked if they wanted to take part in the longitudinal phase of the study, which involved completion of seven postal evaluations over a 5-year period: the baseline evaluation was sent one month after the telephone interview, the second at 6 months and the remaining evaluations scheduled every years. Overall, 3006 completed baseline postal assessment. All participants provided written informed consent to participate in the study, prior to the study protocol and approved by the ethical committee of the Université Laval-Quebec, Canada. The methods in the current study were carried out in accordance with the approved guidelines.
EDS and DS increase during the 5-year follow-up. EDS was assessed at baseline and at each follow-up wave (after 6 months, 1, 2, 3, 4 and 5 years) by the ESS 14 . This scale comprises eight items evaluating sleepiness on a Likert scale from 0 to 3; total scores vary between 0 and 24. A total score >10 indicates EDS, and 15 severe EDS. New cases of EDS between two consecutive visits were defined as participants with EDS at year 't' but without EDS at year 't-1' . Remitted EDS cases were defined as participants without EDS at year 't' but with EDS at year 't-1' , and recurrent EDS cases as participants with EDS at year 't-1' and at year 't' .
In longitudinal analyses, the incidence of EDS was identified from participants without EDS at baseline but who subsequently developed EDS in at least one the follow-up evaluations. Persistent EDS cases were defined as participants reporting EDS at "t"-year follow-up that persists until the end of follow-up. Transient EDS cases was defined as participants reporting EDS at "t"-year follow-up without persistence until the end of follow-up.
A significant increase of DS during the follow-up was defined by at least a 4-point augmentation on the ESS scale between two consecutive evaluations that can or not cross the cut-off of 10. A 4-point change was considered clinically-relevant in previous pharmacological research studies on hypersomnia 17,18 and statistically, it corresponds to the lowest decile of all differences between two consecutive ESS scores. However, an augmentation of 4 points from previous ESS score equal to 0, 1, 2 and 3 was ruled out as considered non-clinically significant (N = 42). Persistent DS increase was defined as the absence of ESS decrease of more than 3-point in the subsequent follow-ups.
A standardized questionnaire was completed relative to diagnosis made by healthcare professionals on sleep disorders including central hypersomnias, insomnia, sleep apnea syndrome, and restless legs syndrome.
Sleep medication including prescriptions and over-the-counter (OTC) drugs used in the previous month were systematically detailed and classified as benzodiazepine (BZD), BZD-like compounds (zolpidem, zopiclone, zaleplon), antidepressants and miscellaneous medications (including barbiturates, OTC, and neuroleptics).  Table 3. Common analyses of the associations between potential predictors and incidences of excessive daytime sleepiness (EDS) and of a 4-point increase of daytime sleepiness (DS) during the 5-year follow-up.
Only baseline ESS score, age, gender and variables associated at p < 0.15 in univariate analysis were entered into the model.

Statistical analysis.
Associations between the characteristics of participants and EDS (ESS > 10 vs. ≤10) at baseline were quantified with odds ratios (OR) and their 95% confidence intervals (CI). Age, gender and other sociodemographic, health behavior and psychological variables associated with EDS at p < 0.15 in bivariate analysis were entered in a logistic regression model to determine which characteristics were independently associated with the presence of EDS. To study which factors were independently associated with EDS severity, three groups of subjects with ESS score ≤10, between 11 and 15 and ≥16 were compared by multinomial logistic regression model with age, gender and factors associated with the severity at p < 0.15. The p-value cut-off choice of 0.15 was based on the recommendations of several authors to use a significance level as high as 0.15, for variable selection in the bivariate analysis because such as 0.05 can fail to identify variables known to be important 36 .
Cox proportional hazard models were used to estimate hazard ratios (HR) and their 95% CI for the associations between potential predictors of a first event of EDS in bivariate analysis. Covariables that appeared or changed during the follow-up were taken into account as time-dependent covariates in the Cox proportional hazard models. The covariate values the year prior to the event time was taken but if this covariate was not updated at an annual visit, then the prior value was carried forward in the time-dependent model. In the case of multiple events during the follow-up, the first event was considered in the analysis. The multivariate analysis, which included age, gender and variables associated at p < 0.15 in the bivariate analysis, was performed using Cox proportional hazard model to evaluate which predictors were independently associated with the incidence of EDS. Similar methodology was performed for the study of predictors of incident DS during the 5-year follow-up. Significance level was set at p < 0.05. Analyses were performed using SAS-version 9.4 (SAS Inc, Cary, NC, USA).