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. 2023 Nov 23:12:RP88359.
doi: 10.7554/eLife.88359.

Sleep regularity and mortality: a prospective analysis in the UK Biobank

Lachlan Cribb  1 , Ramon Sha  1 , Stephanie Yiallourou  1 , Natalie A Grima  1 , Marina Cavuoto  1   2 , Andree-Ann Baril  3 , Matthew P Pase  1   4
Affiliations

Sleep regularity and mortality: a prospective analysis in the UK Biobank

Lachlan Cribb et al. Elife. .

Abstract

Background: Irregular sleep-wake timing may cause circadian disruption leading to several chronic age-related diseases. We examined the relationship between sleep regularity and risk of all-cause, cardiovascular disease (CVD), and cancer mortality in 88,975 participants from the prospective UK Biobank cohort.

Methods: The sleep regularity index (SRI) was calculated as the probability of an individual being in the same state (asleep or awake) at any two time points 24 hr apart, averaged over 7 days of accelerometry (range 0-100, with 100 being perfectly regular). The SRI was related to the risk of mortality in time-to-event models.

Results: The mean sample age was 62 years (standard deviation [SD], 8), 56% were women, and the median SRI was 60 (SD, 10). There were 3010 deaths during a mean follow-up of 7.1 years. Following adjustments for demographic and clinical variables, we identified a non-linear relationship between the SRI and all-cause mortality hazard (p [global test of spline term]<0.001). Hazard ratios, relative to the median SRI, were 1.53 (95% confidence interval [CI]: 1.41, 1.66) for participants with SRI at the 5th percentile (SRI = 41) and 0.90 (95% CI: 0.81, 1.00) for those with SRI at the 95th percentile (SRI = 75), respectively. Findings for CVD mortality and cancer mortality followed a similar pattern.

Conclusions: Irregular sleep-wake patterns are associated with higher mortality risk.

Funding: National Health and Medical Research Council of Australia (GTN2009264; GTN1158384), National Institute on Aging (AG062531), Alzheimer's Association (2018-AARG-591358), and the Banting Fellowship Program (#454104).

Keywords: UK Biobank; actigraphy; circadian rhythms; epidemiology; global health; mortality; none; sleep; sleep regularity.

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Conflict of interest statement

LC, RS, SY, NG, MC, AB, MP No competing interests declared

Figures

Figure 1.
Figure 1.. Adjusted hazard ratios (HRs) for all-cause (A), cardiovascular disease (CVD) (B), and cancer (C) mortality.
p-Values from global (2 degrees of freedom) test of spline term. HRs are relative to the median sleep regularity index (SRI) (SRI = 60). HRs for all-cause mortality, CVD mortality, and cancer mortality were estimated using Cox proportional hazards models, adjusted for age, Townsend deprivation index, sex, antidepressant, antipsychotic, and sedative medication, ethnicity, household income, education, smoking status (former, current, never), smoking pack years, shift work, retirement status, and sick or disabled (self-reported employment category). All continuous confounders and the SRI were modeled with restricted cubic splines (knots at 10th, 50th, and 90th percentiles) to allow for departures from linearity.
Figure 2.
Figure 2.. Cumulative incidence of all-cause mortality across sleep regularity index (SRI).
Standardized cumulative incidence of all-cause mortality for SRI at 41 (5th percentile), 61 (median), and 75 (95th percentile). Estimates from a discrete-time hazards models including an interaction between SRI and time (aggregated into 3-month intervals and modeled with a restricted cubic spline with knots at the 5th, 35th, 65th, and 95th percentiles) and primary model covariates. Confidence intervals were obtained by bootstrapping.
Figure 3.
Figure 3.. Adjusted hazard ratios (HRs) for all-cause mortality for the sleep regularity index (SRI) (A), sleep duration standard deviation (SD) (B), and sleep onset SD (C) measures.
p-Values from global (2 degrees of freedom) test of exposure spline term. HRs are relative to the median SRI (SRI = 60). HRs were estimated using Cox proportional hazards models, adjusted for age, Townsend deprivation index, sex, antidepressant, antipsychotic, and sedative medication, ethnicity, household income, education, smoking status (former, current, never), smoking pack years, shift work, retirement status, and sick or disabled (self-reported employment category). All continuous confounders and the sleep regularity metrics were modeled with restricted cubic splines (knots at 10th, 50th, and 90th percentiles) to allow for departures from linearity.
Appendix 3—figure 1.
Appendix 3—figure 1.. Directed acyclic graph for identification of adjustment variables.
The green node indicates the exposure variable (SRI), and the blue node (Mortality) is the outcome variable. Pale gray nodes indicate unobserved variables; white nodes indicate a variable which has been conditioned on (by regression adjustment or restriction). Paths in red are biasing paths. Arrows indicate the direction of causal effect between two nodes. P is an unobserved variable representing unmeasured causes of sleep habits (e.g., genetics). U is an unobserved variable representing unmeasured causes of disease and cardiovascular dysfunction (e.g., genetics, biological aging). Z is an unobserved variable representing unmeasured causes of health behaviors (e.g., personality factors, genetics). Green paths from SRI to Prevalent disease, BP medication, Systolic BP, BMI, and Physical activity and from these nodes to Mortality represent potential mediation of an SRI effect. Conversely, red paths indicate potential sources of confounding (e.g., a backdoor path from Mortality to Prevalent disease to SRI via U). Given the current evidence base, we are unable to determine whether and to what extent variables such as Prevalent disease act as mediators or confounders (via U) of the SRI-mortality association. AP = anti-psychotic; AD = antidepressant; BMI = body mass index; BP = blood pressure; CVD = cardiovascular disease; Deprivation = the Townsend deprivation index; SRI = sleep regularity index; WASO = wake after sleep onset.
Appendix 3—figure 2.
Appendix 3—figure 2.. Time-varying hazard ratios (HRs) for 5th and 95th percentiles of sleep regularity index (SRI) (relative to median) for all-cause mortality.
(A) HRs for 5th percentile vs median SRI; (B) HRs for 95th percentile vs median SRI. Discrete-time hazards model including time (aggregated into 3-month intervals and modeled with a restricted cubic spline with knots at the 5th, 35th, 65th, and 95th percentiles), SRI, and an SRI by time interaction. Adjusted for age, Townsend deprivation index, sex, antidepressant, antipsychotic, and sedative medication, ethnicity, household income, education, smoking status (former, current, never), smoking pack years, shift work, retirement status, and sick or disabled (self-reported employment category). All continuous confounders and the SRI were modeled with restricted cubic splines (knots at 10th, 50th, and 90th percentiles) to allow for departures from linearity. There was strong evidence of an interaction between time and SRI (p [interaction]<0.001).
Appendix 3—figure 3.
Appendix 3—figure 3.. Time-varying hazard ratios (HRs) for 5th and 95th percentiles of sleep regularity index (SRI) (relative to median) for cancer mortality.
(A) Hazard ratios for 5th percentile vs median SRI; (B) HRs for 95th percentile vs median SRI. Discrete-time hazards model including time (aggregated into 3-month intervals and modeled with a restricted cubic spline with knots at the 5th, 35th, 65th, and 95th percentiles), SRI, and an SRI by time interaction. Adjusted for age, Townsend deprivation index, sex, antidepressant, antipsychotic, and sedative medication, ethnicity, household income, education, smoking status (former, current, never), smoking pack years, shift work, retirement status, and sick or disabled (self-reported employment category). All continuous confounders and the SRI were modeled with restricted cubic splines (knots at 10th, 50th, and 90th percentiles) to allow for departures from linearity. There was strong evidence of an interaction between time and SRI (p [interaction]<0.001).
Appendix 3—figure 4.
Appendix 3—figure 4.. Sleep regularity index (SRI) and cardiovascular disease (CVD)-specific mortality by sex.
Adjusted for age, Townsend deprivation index, antidepressant, antipsychotic, and sedative medication, ethnicity, household income, education, smoking status (former, current, never), smoking pack years, shift work, retirement status, and sick or disabled (self-reported employment category). Hazard ratios are relative to the median SRI (SRI=60).
Appendix 3—figure 5.
Appendix 3—figure 5.. Sleep regularity index (SRI) and all-cause mortality in sensitivity analyses.
p-Values from global (2 degrees of freedom) test of spline term. Hazard ratios (HRs) are relative to the median SRI (SRI = 60). Model 2 (M2) adjustments: Adjusted for age, Townsend deprivation index, sex, antidepressant, antipsychotic, and sedative medication, ethnicity, household income, education, smoking status (former, current, never), smoking pack years, shift work, retirement status, and sick or disabled (self-reported employment category), average sleep time, and average wake after sleep onset time. M2 results: HRs, relative to the median SRI, were 1.42 (95% CI: 1.31, 1.55) and 0.90 (95% CI: 0.80, 1.00) for SRI at the 5th and 95th percentiles, respectively. Model 3 (M3) adjustments: Adjusted for age, Townsend deprivation index, sex, antidepressant, antipsychotic, and sedative medication, ethnicity, household income, education, smoking status (former, current, never), smoking pack years, shift work, retirement status, and sick or disabled (self-reported employment category), and history of diabetes, cancer, mental and behavioral disorder, neurological illness, and cardiovascular illness. M3 results: HRs, relative to the median SRI, were 1.46 (95% CI: 1.35, 1.58) and 0.93 (95% CI: 0.83, 1.03) for the 5th and 95th percentiles of SRI, respectively. Model 4 (M4) adjustments: Model 3 with additional adjustment for body mass index (BMI), moderate and vigorous physical activity, systolic blood pressure, and blood pressure medication. M4 results: HRs, relative to the median SRI, were 1.20 (95% CI: 1.11, 1.31) and 1.00 (95% CI: 0.90, 1.12) for the 5th and 95th percentiles, respectively.
Appendix 3—figure 6.
Appendix 3—figure 6.. Sleep regularity index (SRI) and cardiovascular disease (CVD) mortality in sensitivity analyses.
p-Values from global (2 degrees of freedom) test of spline term. Hazard ratios (HRs) are relative to the median SRI (SRI = 60). Model 2 (M2) adjustments: Adjusted for age, Townsend deprivation index, sex, antidepressant, antipsychotic, and sedative medication, ethnicity, household income, education, smoking status (former, current, never), smoking pack years, shift work, retirement status, and sick or disabled (self-reported employment category), average sleep time, and average wake after sleep onset time. M2 results: HRs were 1.66 (95% CI: 1.40, 1.96) and 0.95 (95% CI: 0.73, 1.22) for the 5th and 95th percentile vs. the median SRI, respectively. Model (M3) adjustments: Adjusted for age, Townsend deprivation index, sex, antidepressant, antipsychotic, and sedative medication, ethnicity, household income, education, smoking status (former, current, never), smoking pack years, shift work, retirement status, and sick or disabled (self-reported employment category), and history of diabetes, cancer, mental and behavioral disorder, neurological illness, and cardiovascular illness. M3 results: HRs were 1.73 (95% CI: 1.47, 2.02) and 0.99 (95% CI: 0.77, 1.26) for the 5th and 95th percentiles, respectively. Model 4 (M4) adjustments: Model 3 with additional adjustment for body mass index (BMI), moderate and vigorous physical activity, systolic blood pressure, and blood pressure medication. M4 results: HRs were somewhat attenuated: 1.43 (95% CI: 1.21, 1.69) and 1.09 (95% CI: 0.85, 1.40), for the 5th and 95th percentiles, respectively.
Appendix 3—figure 7.
Appendix 3—figure 7.. Sleep regularity index (SRI) and cancer mortality in sensitivity analyses.
p-Values from global (2 degrees of freedom) test of spline term. Hazard ratios (HRs) are relative to the median SRI (SRI = 60). Model 2 (M2) adjustments: Adjusted for age, Townsend deprivation index, sex, antidepressant, antipsychotic, and sedative medication, ethnicity, household income, education, smoking status (former, current, never), smoking pack years, shift work, retirement status, and sick or disabled (self-reported employment category), average sleep time, and average wake after sleep onset time. M2 results: HRs were 1.35 (95% CI: 1.20, 1.52) and 0.88 (95% CI: 0.76, 1.02) for the 5th and 95th percentile vs. the median SRI, respectively. Model 3 (M3) adjustments: Adjusted for age, Townsend deprivation index, sex, antidepressant, antipsychotic, and sedative medication, ethnicity, household income, education, smoking status (former, current, never), smoking pack years, shift work, retirement status, and sick or disabled (self-reported employment category), and history of diabetes, cancer, mental and behavioral disorder, neurological illness, and cardiovascular illness. M3 results: HRs were 1.33 (95% CI: 1.19, 1.49) and 0.90 (95% CI: 0.78, 1.04) for the 5th and 95th percentiles, respectively. Model 4 (M4) adjustments: Model 3 with additional adjustment for body mass index (BMI), moderate and vigorous physical activity, systolic blood pressure, and blood pressure medication. M4 results: HRs were 1.15 (95% CI: 1.02, 1.30) and 0.97 (95% CI: 0.84, 1.12) for the 5th and 95th percentiles, respectively.
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