NOS1基因变异与失眠、睡眠时长以及阻塞性睡眠呼吸暂停临床数量性状的相关性

doi:10.3969/j.issn.1674-8115.2024.12.002

上海交通大学学报（医学版） ›› 2024, Vol. 44 ›› Issue (12): 1490-1503.doi: 10.3969/j.issn.1674-8115.2024.12.002

• 论著 · 基础研究 • 上一篇

NOS1基因变异与失眠、睡眠时长以及阻塞性睡眠呼吸暂停临床数量性状的相关性

袁灏琳(), 李念念, 胡珺晖, 沈锦虹, 高振飞, 关建, 刘峰, 殷善开()

上海交通大学医学院附属第六人民医院耳鼻咽喉头颈外科，上海市睡眠呼吸障碍疾病重点实验室，上海 200233

收稿日期:2024-04-12 接受日期:2024-05-21 出版日期:2024-12-25 发布日期:2024-12-25
通讯作者: 殷善开 E-mail:hlyuan78@126.com;skyin@sjtu.edu.cn
作者简介:袁灏琳（1995—），女，硕士生；电子信箱：hlyuan78@126.com。
基金资助:
科技创新2030—重大项目(2021ZD0201900);国家自然科学基金(82100105);上海市科学技术委员会项目(18DZ2260200)

Association of genetic variations in the NOS1 gene with insomnia, sleep duration and obstructive sleep apnea-related clinical quantitative traits

YUAN Haolin(), LI Niannian, HU Junhui, SHEN Jinhong, GAO Zhenfei, GUAN Jian, LIU Feng, YIN Shankai()

Department of Otorhinolaryngology Head and Neck Surgery, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai 200233, China

Received:2024-04-12 Accepted:2024-05-21 Online:2024-12-25 Published:2024-12-25
Contact: YIN Shankai E-mail:hlyuan78@126.com;skyin@sjtu.edu.cn
Supported by:
Science and Technology Innovation 2030?Major Project(2021ZD0201900);National Natural Science Foundation of China(82100105);Project of Shanghai Municipal Commission of Science and Technology(18DZ2260200)

摘要/Abstract

摘要：

目的·探索神经型一氧化氮合酶（nitric oxide synthase 1，NOS1）遗传变异rs7305526和rs11615756与失眠、睡眠时长和阻塞性睡眠呼吸暂停（obstructive sleep apnea，OSA）临床数量性状的相关性。方法·利用Allen Human Brain Atlas数据集分析NOS1基因在人类全脑水平的表达模式，通过表达数量性状位点分析rs7305526和rs11615756对NOS1基因表达的影响。利用英国生物银行（United Kingdom Biobank，UKB）的全基因组关联研究（Genome Wide Association Study，GWAS）数据集，采用回归分析探讨rs7305526和rs11615756与失眠及睡眠时长2种睡眠性状的相关性。利用上海睡眠健康队列研究（Shanghai Sleep Health Study Cohort，SSHS）基于标准多导睡眠监测（polysomnography，PSG）的临床监测数据，分析rs7305526和rs11615756与OSA临床数量性状（包括呼吸、血氧和睡眠结构性状）的相关性。结果·NOS1基因在睡眠调节脑区（杏仁核、基底前脑、纹状体和丘脑）和呼吸中枢（间脑和脑桥被盖部）的部分核团呈较高的表达水平，而在大脑和小脑皮层、脑桥等区域呈低水平的表达或不表达。rs7305526和rs11615756与NOS1在大脑皮层的表达水平均呈显著负相关，此外rs11615756同样与杏仁核中NOS1的表达水平呈显著负相关。UKB GWAS数据显示rs7305526与失眠、睡眠时长无显著相关，而rs11615756仅与睡眠时长呈显著负相关。SSHS临床监测数据显示，rs7305526与最低血氧饱和度（lowest pulse blood oxygen saturation，LSpO₂）、呼吸暂停低通气指数和非快速眼动睡眠（non-rapid eye movement，NREM）2期时间占比等OSA临床数量性状的变化显著相关。虽然rs11615756仅与NREM 2和3期次数呈显著负相关，但在根据OSA严重程度分层后，rs11615756和rs7305526与部分呼吸血氧性状存在显著相关性。结论·NOS1基因变异与人类睡眠时长性状和OSA呼吸、血氧、睡眠结构性状存在显著关联，rs7305526（C>A）对睡眠性状的调节独立于对呼吸、血氧的调节。

关键词: 阻塞性睡眠呼吸暂停, NOS1基因, 人类睡眠, 临床数量性状, 遗传变异

Abstract:

Objective ·To explore the correlation between the genetic variations rs7305526 and rs11615756 of nitric oxide synthase 1 (NOS1) and the human sleep traits, including insomnia, sleep duration, and clinical quantitative traits related to obstructive sleep apnea (OSA). Methods ·The NOS1 gene expression pattern at the whole-brain level using the Allen Human Brain Atlas dataset was analyzed. Subsequently, we performed expression quantitative trait locus (eQTL) analysis to investigate the impact of rs7305526 and rs11615756 on NOS1 gene expression. Regression analysis was conducted to assess the associations between rs7305526 and rs11615756 with insomnia and sleep duration based on the United Kingdom Biobank (UKB) Genome-Wide Association Study (GWAS) dataset. Furthermore, we explored the relationships between rs7305526 and rs11615756 with clinical quantitative traits of OSA, such as respiratory events, oxygen levels, and sleep traits, using clinical monitoring data from the Shanghai Sleep Health Study Cohort (SSHS) based on standard polysomnography (PSG). Results ·The NOS1 genedemonstrated elevated levels of expression in various brain regions crucial for regulating sleep, namely the amygdala, basal forebrain, striatum, and thalamus, as well as in the respiratory center, including the mesencephalon and pontine tegmentum. In contrast, the expression level of NOS1 gene was significantly reduced or absent in areas such as the cerebral cortex and cerebellum. Variants rs7305526 and rs11615756 were significantly negatively correlated with the expression levels of NOS1 in the cerebral cortex. Additionally, rs11615756 was also significantly negatively correlated with the expression level of NOS1 in the amygdala. Analysis of the UKB GWAS data revealed that the variant rs7305526 was not significantly associated with either insomnia or sleep duration, while rs11615756 demonstrated a noteworthy negative correlation specifically with sleep duration. Data obtained from the SSHS indicated a significant association between rs7305526 and alterations in clinical quantitative traits of OSA, including lowest pulse blood oxygen saturation (LSpO₂), apnea-hypopnea index (AHI), and the ratio of non-rapid eye movement (NREM) stage 2 sleep duration. Although rs11615756 showed a notable negative correlation solely with the quantity of NREM stages 2 and 3, both rs11615756 and rs7305526 showed significant correlations with some respiratory events and oxygen traits after stratification according to the severity of OSA. Conclusion ·Genetic variants of NOS1 gene are respectively associated with human sleep duration traits and OSA-related variables, suggesting that NOS1 gene plays a crucial regulatory role in human sleep and clinical quantitative traits of OSA. The regulation of sleep traits by rs7305526 (C>A) is independent of its regulation of respiratory events and oxygen traits.

Key words: obstructive sleep apnea (OSA), nitric oxide synthase 1 (NOS1)gene, human sleep, clinical quantitative trait, genetic variation

中图分类号:

R762

袁灏琳, 李念念, 胡珺晖, 沈锦虹, 高振飞, 关建, 刘峰, 殷善开. NOS1基因变异与失眠、睡眠时长以及阻塞性睡眠呼吸暂停临床数量性状的相关性[J]. 上海交通大学学报（医学版）, 2024, 44(12): 1490-1503.

YUAN Haolin, LI Niannian, HU Junhui, SHEN Jinhong, GAO Zhenfei, GUAN Jian, LIU Feng, YIN Shankai. Association of genetic variations in the NOS1 gene with insomnia, sleep duration and obstructive sleep apnea-related clinical quantitative traits[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(12): 1490-1503.

图/表 12

参考文献 26

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SNP	Tissue	Effect size	P value
rs7305526	Brain cortex	-0.127	0.044
	Lung	-0.136	<0.001
	Tibial nerve	0.178	<0.001
	Colon sigmoid	-0.061	0.039
	Heart atrial appendage	-0.155	0.014
	Minor salivary gland	0.141	0.033
	Thyroid	0.099	0.049
rs11615756	Brain amygdala	-0.224	0.008
	Brain cortex	-0.151	0.028
	Esophagus mucosa	-0.084	0.031
	Thyroid	0.104	0.049
	Skeletal muscle	0.061	0.017
	Pancreas	0.114	0.020

SNP	Tissue	Effect size	P value
rs7305526	Brain cortex	-0.127	0.044
	Lung	-0.136	<0.001
	Tibial nerve	0.178	<0.001
	Colon sigmoid	-0.061	0.039
	Heart atrial appendage	-0.155	0.014
	Minor salivary gland	0.141	0.033
	Thyroid	0.099	0.049
rs11615756	Brain amygdala	-0.224	0.008
	Brain cortex	-0.151	0.028
	Esophagus mucosa	-0.084	0.031
	Thyroid	0.104	0.049
	Skeletal muscle	0.061	0.017
	Pancreas	0.114	0.020

Sleep trait	GWAS catalog accession	PMID	Author and year	Population	Number
Insomnia	GCST004695	28604731	HAMMERSCHLAG 2017	European (UK)	113 006
	GCST90267286	37106081	SCHOELER 2023	European (UK)	283 595
Sleep duration	GCST003839	27494321	JONES 2016	European (UK)	127 573
	GCST006914	30531941	DOHERTY 2018	European (UK)	91 105
	GCST007561	30846698	DASHTI 2019	European (UK)	446 118

Sleep trait	GWAS catalog accession	PMID	Author and year	Population	Number
Insomnia	GCST004695	28604731	HAMMERSCHLAG 2017	European (UK)	113 006
	GCST90267286	37106081	SCHOELER 2023	European (UK)	283 595
Sleep duration	GCST003839	27494321	JONES 2016	European (UK)	127 573
	GCST006914	30531941	DOHERTY 2018	European (UK)	91 105
	GCST007561	30846698	DASHTI 2019	European (UK)	446 118

Variable	Overall (n=6 026)	AA (n=1 941)	CA (n=2 867)	CC (n=1 077)	P value
Genotype/n(%)					<0.001
AA	1 941 (32.2)	1 941 (100.0)	0 (0)	0 (0)
CA	2 867 (47.6)	0 (0)	2 867 (100.0)	0 (0)
CC	1 077 (17.9)	0 (0)	0 (0)	1 077 (100.0)
NA	141 (2.3)	0 (0)	0 (0)	0 (0)
Gender/n(%)					0.175
Male	5 325 (88.4)	1 699 (87.5)	2 538 (88.5)	967 (89.8)
Female	701 (11.6)	242 (12.5)	329 (11.5)	110 (10.2)
Smoking status/n(%)					0.924
Never	3 926 (65.2)	1 262 (65.0)	1 872 (65.3)	708 (65.7)
Ever	2 100 (34.8)	679 (35.0)	995 (34.7)	369 (34.3)
Drinking status/n(%)					0.862
Never	3 637 (60.4)	1 181 (60.8)	1 722 (60.1)	650 (60.4)
Ever	2 389 (39.6)	760 (39.2)	1 145 (39.9)	427 (39.6)
AHI (events/h)^①/n(%)					<0.001
AHI< 5 (Non-OSA)	764 (12.7)	212 (10.9)	360 (12.6)	173 (16.1)
5 ≤AHI < 15 (Mild-OSA)	318 (5.3)	90 (4.6)	161 (5.6)	63 (5.9)
15 ≤AHI < 30 (Moderate-OSA)	1 245 (20.7)	407 (21.0)	577 (20.1)	235 (21.9)
≥30 (Severe-OSA)	3 692 (61.3)	1 231 (63.4)	1 766 (61.6)	603 (56.1)
T2DM status/n(%)					0.787
No	5 580 (92.6)	1 790 (92.2)	2 658 (92.7)	999 (92.8)
Yes	446 (7.4)	151 (7.8)	209 (7.3)	78 (7.2)
Hypertension status/n(%)					0.761
No	5 141 (85.3)	1 649 (85.0)	2 452 (85.5)	925 (85.9)
Yes	885 (14.7)	292 (15.0)	415 (14.5)	152 (14.1)

NOS1基因变异与失眠、睡眠时长以及阻塞性睡眠呼吸暂停临床数量性状的相关性

Association of genetic variations in the NOS1 gene with insomnia, sleep duration and obstructive sleep apnea-related clinical quantitative traits

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参考文献 26

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Metrics

Variable	Overall (n=6 026)	CC (n=3 352)	TC (n=2 236)	TT (n=385)	P value
Genotype/n(%)					<0.001
CC	3 352 (55.6)	3 352 (100.0)	0 (0)	0 (0)
TC	2 236 (37.1)	0 (0)	2 236 (100.0)	0 (0)
TT	3 85 (6.4)	0 (0)	0 (0)	385 (100.0)
NA	53 (0.9)	0 (0)	0 (0)	0 (0)
Gender/n(%)					0.027
Male	5 325 (88.4)	2 965 (88.5)	1 956 (87.5)	355 (92.2)
Female	701 (11.6)	387 (11.5)	280 (12.5)	30 (7.8)
Smoking status/n(%)					0.599
Never	3 926 (65.2)	2 183 (65.1)	1 465 (65.5)	242 (62.9)
Ever	2 100 (34.8)	1 169 (34.9)	771 (34.5)	143 (37.1)
Drinking status/n(%)					0.513
Never	3 637 (60.4)	2 004 (59.8)	1 371 (61.3)	231 (60.0)
Ever	2 389 (39.6)	1 348 (40.2)	865 (38.7)	154 (40.0)
AHI (events/h)^①/n(%)					0.685
AHI< 5 (Non-OSA)	764 (12.7)	421 (12.6)	293 (13.1)	44 (11.4)
5 ≤AHI < 15 (Mild-OSA)	318 (5.3)	184 (5.5)	109 (4.9)	22 (5.7)
15 ≤AHI < 30 (Moderate-OSA)	1 245 (20.7)	700 (20.9)	459 (20.6)	70 (18.2)
≥30 (Severe-OSA)	3 692 (61.3)	2 044 (61.0)	1 371 (61.4)	249 (64.7)
T2DM status/n(%)					0.989
No	5 580 (92.6)	3 104 (92.6)	2 072 (92.7)	356 (92.5)
Yes	446 (7.4)	248 (7.4)	164 (7.3)	29 (7.5)
Hypertension status/n(%)					0.568
No	5 141 (85.3)	2 863 (85.4)	1 896 (84.8)	334 (86.8)
Yes	885 (14.7)	489 (14.6)	340 (15.2)	51 (13.2)

SNP	Genotype	Ratio of individuals of each genotype/%
SNP	Genotype	Non-OSA	OSA
rs7305526	AA	28.46	33.66
	CA	48.32	48.78
	CC	23.22	17.55
rs11615756	CC	55.54	56.22
	TC	38.65	37.23
	TT	5.80	6.55

SNP	Allele	Trait	OR	95%CI		P value
SNP	Allele	Trait	OR	Lower	Upper	P value
rs7305526	C>A	AHI_total	0.126	0.049	0.326	<0.001
		AHI_REM	0.189	0.071	0.502	<0.001
		AHI_NREM	0.153	0.057	0.415	<0.001
		ODI	0.111	0.040	0.313	<0.001
		LT90	0.008	0.001	0.188	0.003
		LT80	0.160	0.027	0.964	0.046
		LT70	0.436	0.192	0.990	0.047
		LSpO₂	4.455	2.548	7.784	<0.001
		SSS	0.866	0.787	0.954	0.004
		WK(TIB) frequency	1.239	1.011	1.517	0.039
		WK(TIB) duration	34.022	3.300	350.724	0.003
		WK/TIB	1.848	1.136	3.007	0.013
		N2 frequency	0.818	0.446	1.500	0.515
		N2/TIB	0.482	0.258	0.901	0.022
		N3 frequency	0.861	0.501	1.477	0.586
rs11615756	T>C	AHI_total	1.352	0.464	3.939	0.581
		AHI_REM	1.578	0.521	4.783	0.420
		AHI_NREM	0.862	0.280	2.658	0.796
		ODI	1.225	0.381	3.939	0.733
		LT90	0.032	0.001	1.165	0.061
		LT80	0.512	0.067	3.908	0.519
		LT70	0.911	0.361	2.301	0.844
		LSpO₂	0.946	0.501	1.785	0.864
		SSS	1.025	0.919	1.143	0.661
		WK(TIB) frequency	0.880	0.700	1.107	0.275
		WK(TIB) duration	1.690	0.120	23.712	0.697
		WK/TIB	1.204	0.693	2.091	0.510
		N2 frequency	0.364	0.184	0.720	0.004
		N2/TIB	0.737	0.355	1.533	0.414
		N3 frequency	0.440	0.240	0.807	0.008

Gender	SNP	Allele	Trait	OR	95%CI		P value
Gender	SNP	Allele	Trait	OR	Lower	Upper	P value
Male	rs7305526	C>A	AHI_total	0.103	0.037	0.285	<0.001
			AHI_REM	0.189	0.066	0.535	0.002
			AHI_NREM	0.111	0.038	0.322	<0.001
			ODI	0.093	0.031	0.281	<0.001
			LT90	0.004	0.001	0.116	0.001
			LT80	0.177	0.029	1.087	0.061
			LT70	0.540	0.252	1.154	0.112
			LSpO₂	4.782	2.821	8.108	<0.001
			SSS	0.865	0.781	0.958	0.006
			WK (TIB) frequency	1.215	0.979	1.508	0.078
			WK (TIB) duration	36.696	3.154	426.991	0.004
			WK/TIB	2.002	1.208	3.318	0.007
			N2 frequency	0.781	0.412	1.482	0.450
			N2/TIB	0.129	0.006	2.867	0.195
			N3 frequency	2.881	0.268	30.958	0.382
	rs11615756	T>C	AHI_total	1.251	0.398	3.929	<0.001
			AHI_REM	1.246	0.385	4.039	0.002
			AHI_NREM	0.890	0.268	2.962	<0.001
			ODI	1.049	0.303	3.638	<0.001
			LT90	0.049	0.001	2.051	0.001
			LT80	0.369	0.047	2.868	0.061
			LT70	0.748	0.317	1.764	0.112
			LSpO₂	1.159	0.638	2.105	<0.001
			SSS	1.020	0.909	1.144	0.006
			WK (TIB) frequency	0.862	0.676	1.100	0.078
			WK (TIB) duration	4.212	0.264	67.122	0.004
			WK/TIB	1.430	0.808	2.531	0.007
			N2 frequency	0.356	0.174	0.726	0.450
			N2/TIB	0.823	0.025	27.424	0.195
			N3 frequency	0.197	0.014	2.876	0.382
Female	rs7305526	C>A	AHI_total	0.726	0.060	8.786	0.801
			AHI_REM	0.371	0.025	5.499	0.471
			AHI_NREM	1.586	0.106	23.735	0.738
			ODI	0.761	0.045	12.926	0.850
			LT90	0.238	0.002	5 373.921	0.779
			LT80	0.128	0.001	195.286	0.581
			LT70	0.163	0.006	4.516	0.283
			LSpO₂	1.137	0.266	4.854	0.862
			SSS	0.846	0.635	1.127	0.253
			WK (TIB) frequency	1.352	0.766	2.384	0.298
			WK (TIB) duration	26.286	0.017	41 622.230	0.384
			WK/TIB	1.857	0.394	8.760	0.434
			N2 frequency	1.020	0.152	6.841	0.984
			N2/TIB	0.002	0.001	2.374	0.078
			N3 frequency	11.913	0.017	8 142.930	0.456
	rs11615756	T>C	AHI_total	3.274	0.174	61.738	0.428
			AHI_REM	19.344	0.799	468.319	0.068
			AHI_NREM	0.808	0.034	19.383	0.895
			ODI	5.700	0.202	161.096	0.307
			LT90	0.004	0.001	716.665	0.375
			LT80	14.017	0.003	65 377.371	0.539
			LT70	20.663	0.444	960.811	0.122
			LSpO₂	0.397	0.073	2.162	0.285
			SSS	1.092	0.781	1.529	0.606
			WK (TIB) frequency	1.047	0.537	2.040	0.893
			WK (TIB) duration	0.002	0.001	3.107	0.088
			WK/TIB	0.303	0.049	1.871	0.198
			N2 frequency	0.546	0.057	5.229	0.599
			N2/TIB	0.093	0.001	2 235.485	0.644
			N3 frequency	0.096	0.001	201.306	0.547

SNP	Trait	Non-OSA (n=764)		Mild-OSA (n=318)		Moderate-OSA (n=1 245)		Severe-OSA (n=3 692)
SNP	Trait	P value	OR (95%CI)	P value	OR (95%CI)	P value	OR (95%CI)	P value	OR (95%CI)
rs7305526	AHI_total	0.530	0.955 (0.826‒1.104)	0.290	0.818 (0.563‒1.188)	0.619	1.090 (0.777‒1.528)	0.206	0.593 (0.264‒1.334)
	AHI_REM	0.763	1.176 (0.410‒3.380)	0.965	1.070 (0.054‒21.232)	0.890	0.894 (0.182‒4.383)	0.577	0.749 (0.271‒2.070)
	AHI_NREM	0.464	1.461 (0.529‒4.0332)	0.143	4.276 (0.611‒29.910)	0.846	1.076 (0.517‒2.239)	0.206	0.538 (0.205‒1.408)
	ODI	0.821	0.847 (0.199‒3.602)	0.562	1.330 (0.505‒3.501)	0.124	0.516 (0.222‒1.200)	0.464	0.684 (0.247‒1.892)
	LT90	0.633	0.536 (0.041‒6.958)	0.036	23.117 (1.232‒433.679)	0.632	1.864 (0.146‒23.881)	0.122	0.032 (0.001‒2.517)
	LT80	0.982	0.999 (0.907‒1.100)	0.097	1.397 (0.941‒2.074)	0.678	0.878 (0.475‒1.624)	0.392	0.290 (0.017‒4.948)
	LT70	0.278	0.998 (0.993‒1.002)	0.613	0.990 (0.951‒1.030)	0.331	1.064 (0.939‒1.205)	0.179	0.424 (0.121‒1.481)
	LSpO₂	0.019	2.039 (1.124‒3.699)	0.958	1.028 (0.372‒2.841)	0.022	2.280 (1.129‒4.605)	0.008	2.217 (1.226‒4.011)
	SSS	0.421	0.888 (0.666‒1.186)	0.333	1.193 (0.834‒1.706)	0.995	1.001 (0.817‒1.226)	0.153	0.923 (0.826‒1.030)
	WK (TIB) frequency	0.215	1.498 (0.791‒2.838)	0.016	0.369 (0.163‒0.832)	0.130	1.432 (0.900‒2.281)	0.244	1.158 (0.905‒1.4811)
	WK (TIB) duration	0.119	406.376 (0.213‒775 370.391)	0.606	0.060 (0.001‒2674.448)	0.046	269.283 (1.095‒66 255.145)	0.230	5.352 (0.345‒83.043)
	WK/TIB	0.097	3.846 (0.784‒18.871)	0.714	0.661 (0.072‒6.081)	0.142	2.251 (0.763‒6.641)	0.240	1.411 (0.794‒2.508)
	N2 frequency	0.788	0.857 (0.277‒2.650 6)	0.432	0.454 (0.063‒3.278)	0.921	0.942 (0.289‒3.071)	0.892	0.942 (0.398‒2.230)
	N2/TIB	0.214	0.009 (0.001‒15.720)	0.035	0.002 (0.001‒0.405)	0.678	0.272 (0.001‒128.335)	0.695	0.462 (0.010‒21.825)
	N3 frequency	0.295	0.045 (0.001‒14.873)	0.021	10 267.538 (3.963‒26 600 123.192)	0.528	4.297 (0.046‒400.757)	0.648	2.015 (0.099‒40.930)
rs11615756	AHI_total	0.777	0.976 (0.823‒1.157)	0.875	0.968 (0.639‒1.464)	0.626	1.104 (0.742‒1.642)	0.626	0.801 (0.328‒1.957)
	AHI_REM	0.027	0.251 (0.074‒0.856)	0.791	1.551 (0.060‒40.217)	0.085	5.121 (0.800‒32.802)	0.750	1.202 (0.389‒3.711)
	AHI_NREM	0.029	0.270 (0.083‒0.875)	0.504	0.500 (0.065‒3.838)	0.392	1.457 (0.616‒3.448)	0.377	0.620 (0.214‒1.793)
	ODI	0.123	0.266 (0.050‒1.429)	0.846	1.112 (0.381‒3.249)	0.840	1.108 (0.411‒2.98)	0.994	1.004 (0.327‒3.080)
	LT90	0.511	2.705 (0.139‒52.722)	0.076	0.053 (0.002‒1.364)	0.324	4.571 (0.222‒93.989)	0.006	0.002 (0.001‒0.148)
	LT80	0.407	0.952 (0.848‒1.069)	0.757	1.074 (0.682‒1.690)	0.077	1.885 (0.933‒3.807)	0.290	0.184 (0.008‒4.251)
	LT70	0.314	0.997 (0.992‒1.003)	0.565	0.987 (0.943‒1.033)	0.035	1.166 (1.011‒1.344)	0.857	0.881 (0.221‒3.504)
	LSpO₂	0.951	1.022 (0.511‒2.046)	0.314	1.780 (0.577‒5.489)	0.480	0.743 (0.326‒1.696)	0.357	1.362 (0.706‒2.627)
	SSS	0.697	1.070 (0.762‒1.501)	0.019	0.626 (0.423‒0.926)	0.949	0.992 (0.782‒1.259)	0.435	1.050 (0.929‒1.186)
	WK (TIB) frequency	0.238	0.636 (0.300‒1.349)	0.835	1.101 (0.444‒2.731)	0.917	0.971 (0.561‒1.682)	0.470	0.905 (0.689‒1.188)
	WK (TIB) duration	0.397	46.583 (0.006‒338 729.248)	0.531	43.721 (0.001‒6 081 353.502)	0.772	0.381 (0.001‒256.719)	0.879	1.266 (0.061‒26.225)
	WK/TIB	0.456	2.041 (0.313‒13.327)	0.661	1.729 (0.148‒20.150)	0.845	0.881 (0.245‒3.167)	0.517	1.234 (0.653‒2.331)
	N2 frequency	0.135	0.366 (0.098‒1.370)	0.934	0.911 (0.099‒8.373)	0.918	0.930 (0.234‒3.703)	0.005	0.261 (0.101‒0.671)
	N2/TIB	0.091	2 007.782 (0.296‒13 627 828.272)	0.832	3.998 (0.001‒1 516 906.783)	0.407	0.046 (0.001‒66.068)	0.498	0.228 (0.003‒16.421)
	N3 frequency	0.979	1.094 (0.001‒976.421)	0.665	0.145 (0.001‒929.697)	0.778	0.464 (0.002‒96.210)	0.173	0.098 (0.004‒2.775)

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