Epidemiology and Global Health

Sleep Regularity and Mortality: A Prospective Analysis in the UK Biobank

Lachlan Cribb
Ramon Sha
Stephanie Yiallourou
Natalie A Grima
Marina Cavuoto
Andree-Ann Baril
Matthew P. Pase author has email address

Turner Institute for Brain and Mental Health, Monash University, Melbourne Australia
National Ageing Research Institute, Melbourne, Australia
Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada
Harvard T.H. Chan School of Public Health, Harvard University, MA, USA

https://doi.org/10.7554/eLife.88359.2

Open access
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Figures and data

Sample characteristics (n = 88,975)

Adjusted hazard ratios for all-cause (A), CVD (B), and cancer (C) mortality.
P values from global (2 degree of freedom) test of spline term. Hazard ratios (HR) are relative to the median 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 10^th, 50^th, and 90^th percentiles) to allow for departures from linearity.

Cumulative incidence of all-cause mortality across SRI.
Standardized cumulative incidence of all-cause mortality for SRI at 41 (5^th percentile), 61 (median), and 75 (95^th 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 5^th, 35^th, 65^th, and 95^th percentiles) and primary model covariates. Confidence intervals were obtained by bootstrapping.

Adjusted hazard ratios for all-cause mortality for the SRI (A), sleep duration SD (B), and sleep onset SD (C) measures.
P values from global (2 degree of freedom) test of exposure spline term. Hazard ratios (HR) 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 10^th, 50^th, and 90^th percentiles) to allow for departures from linearity.

Correlation between sleep regularity index and standard deviation-based regularity metrics

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 grey 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 ageing). Z is an unobserved variable representing unmeasured causes of health behaviours (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.

Time-varying HRs for 5^th and 95^th percentiles of SRI (relative to median) for all-cause mortality.
A: Hazard ratios for 5^th percentile vs median SRI; B: Hazard ratios for 95^th percentile vs median SRI. Discrete time hazards model including time (aggregated into 3-month intervals and modelled with a restricted cubic spline with knots at the 5^th, 35^th, 65^th, and 95^th 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 modelled with restricted cubic splines (knots at 10^th, 50^th, and 90^th percentiles) to allow for departures from linearity. There was strong evidence of an interaction between time and SRI (p [interaction] < 0.001).

Time-varying HRs for 5^th and 95^th percentiles of SRI (relative to median) for cancer-mortality.
A: Hazard ratios for 5^th percentile vs median SRI; B: Hazard ratios for 95^th percentile vs median SRI. Discrete time hazards model including time (aggregated into 3-month intervals and modelled with a restricted cubic spline with knots at the 5^th, 35^th, 65^th, and 95^th 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 modelled with restricted cubic splines (knots at 10^th, 50^th, and 90^th percentiles) to allow for departures from linearity. There was strong evidence of an interaction between time and SRI (p [interaction] < 0.001).

SRI and 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).

SRI and all-cause mortality in sensitivity analyses.
P values from global (2 degree of freedom) test of spline term. Hazard ratios 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 5^th and 95^th 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 past or prevalent diabetes, cancer, mental and behavioural 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 5^th and 95^th percentiles of SRI, respectively.
Model 4 (M4) adjustments: Model 3 with additional adjustment for 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 5^th and 95^th percentiles, respectively.

SRI and CVD-mortality in sensitivity analyses.
P values from global (2 degree of freedom) test of spline term. Hazard ratios 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 5^th and 95^th 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 past or prevalent diabetes, cancer, mental and behavioural 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 5^th and 95^th percentiles, respectively.
Model 4 (M4) adjustments: Model 3 with additional adjustment for 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 5^th and 95^th percentiles, respectively.

SRI and cancer-mortality in sensitivity analyses.
P values from global (2 degree of freedom) test of spline term. Hazard ratios 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 5^th and 95^th 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 past or prevalent diabetes, cancer, mental and behavioural 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 5^th and 95^th percentiles, respectively.
Model 4 (M4) adjustments: Model 3 with additional adjustment for 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 5^th and 95^th percentiles, respectively.

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