Determinants and Time Trends for Ischaemic and Haemorrhagic Stroke in a Large Chinese Population
Determinants and Time Trends for Ischaemic and Haemorrhagic Stroke in a Large Chinese Population
Yutao Guo 0 1 2 3 4
Hao Wang 0 1 2 3 4
Tao Tao 0 1 2 3 4
Yingchun Tian 0 1 3 4
Yutang Wang 0 1 2 3 4
Yundai Chen 0 1 2 3 4
Gregory Y. H. Lip 0 1 3 4
0 Funding: The study was supported by Chinese PLA Healthcare Foundation (13BJZ40) , Beijing Natural Science Foundation (7142149) , and National Natural Science Foundation of China , H2501
1 Data Availability Statement: The database in this study was held by the government of Yunnan Province, China, which was managed and contacted with Center for Medical Insurance, Human Resources and Social Security , Yunnan
2 Department of Cardiology, Chinese PLA General Hospital , Beijing , China , 2 Department of Gerontology, Second People's Hospital , Kunming, Yunnan Province , China , 3 University of Birmingham Centre for Cardiovascular Sciences, City Hospital , Birmingham , United Kingdom
3 Editor: Jinglu Ai, University of Toronto , CANADA
4 Competing Interests: Professor Lip has served as a consultant for Bayer , Astellas, Merck, Sanofi, BMS/Pfizer, Daiichi-Sankyo, Biotronik, Portola
Methods The clinical epidemiology of stroke has been widely investigated in Caucasian populations, but the changes over time in the proportion of ischaemic to haemorrhagic strokes is less clear, especially in the Chinese population. Our objective was to study the determinants and time trends for ischaemic and haemorrhagic stroke, in relation to age, in a large Chinese population cohort. Using a medical insurance database in the southwest of China from 2001 to 2012, time trends in age-adjusted ischaemic and haemorrhagic stroke incidence and the contributing risk factors associated with age were investigated. Among 425,901 individuals without prior stroke (52.4% male, median age 54), the rate of ischaemic stroke (per 1000 patient-years) decreased between 2002±2007, then remained broadly similar between 2008±2012. The rate of haemorrhagic stroke showed a similar trend, being approximately 1.3±1.9 from 2008±2012. Compared to patients age<65, ischaemic and haemorrhagic stroke incidences (rate, 95% confidential interval, CI) were higher in the elderly population (age <65 versus age 65: ischaemic: 3.64, 3.33±4.00, vs 14.33, 14.01±14.60; haemorrhagic: 1.09, 1.00±1.10 vs 2.52,2.40±2.70, respectively, both p<0.001). There were no significant differences in haemorrhagic stroke rates between the elderly and the very elderly population. Ischaemic and haemorrhagic stroke shared similar risk factors (age, hypertension, coronary artery disease (CAD), vascular disease, and diabetes mellitus) (all p<0.05). In subjects age<75 years, CAD (7.17, 4.14±12.37) and
Medtronic, Daiichi-Sankyo and Boehringer
Ingelheim and has been on the speaker's bureau
for Bayer, BMS/Pfizer, Boehringer Ingelheim,
Daiichi-Sankyo, Medtronic and Sanofi Aventis.
Other authors ± none declared, as relevant to this
diabetes mellitus (3.27, 2.42±4.42) contributed most to the developing of haemorrhagic
stroke (all p<0.001). Amongst the very elderly, vascular disease (2.24, 1.49±3.37) was an
additional major risk factor for haemorrhagic stroke, together with CAD and diabetes
mellitus (all p<0.001).
In this large Chinese cohort, there was an increased risk of ischaemic stroke compared to
haemorrhagic stroke with ageing. CAD, vascular disease, diabetes mellitus, and
hypertension were major contributors to the development of hemorrhagic stroke in the very elderly
The prevalence, incidence, and life-time risk of ischaemic stroke have been investigated widely
], and major risk factors (i.e. atrial fibrillation, AF) for ischaemic stroke have been identified
]. Of these, there is a cumulative impact of multiple risk factors for ischaemic stroke risk [
Much interest has been focused on ischemic stroke but amongst Asian subjects, there is a
greater risk of haemorrhagic stroke (i.e. intracerebral hemorrhage (ICH), subarachnoid
hemorrhage (SAH)) compared to non-Asians [
]. Of all strokes, ICH accounts for 10% and is
associated with major disability and higher fatality [
], leading to a greater global burden.
Haemorrhagic stroke incidence and mortality are significantly greater in developing countries
compared to developed countries [
Overall stroke incidence in low-income and middle-income countries exceeds that seen in
high-income countries by 20% in the 21st century [
]. The burden of stroke is particularly
serious in Asia, and stroke mortality in Asia is even higher than in Europe or North America [
On the other hand, stroke incidence rates have fallen by 42% in high-income countries over
past 4 decades, as has the stroke mortality [
]. This fall may be helped by antithrombotic
therapy for ischaemic stroke prevention, based on the net clinical benefit balancing ischaemic and
haemorrhagic events. This balance would be difficult in the elderly, who are at high risk for
both ischaemic and haemorrhagic stroke. However, Asian subjects have a significant increase
in ICH incidence compared to the Caucasian population [
], with a four-fold increased risk
for ICH whilst on warfarin therapy [
The clinical epidemiology of stroke has been widely investigated in Caucasian populations,
but the changes over time in the proportion of ischaemic to haemorrhagic strokes is less clear,
especially in developing countries from Asia [
]. Our objective was to study the determinants,
time trends and relation to age, for first-ever ischaemic and haemorrhagic stroke, in a large
Chinese population cohort over a 10-year observational period.
Databases used in this study have previously been described in detail [
]. The Chinese
National Health Insurance program, which includes the Chinese medical insurance scheme,
and Rural Cooperative Medical System, provide the basic medical care to urban and rural
residents. The Chinese medical insurance scheme was started in December, 1998, and this
program provides coverage for inpatient and outpatient medical services to approximately 597
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million Chinese urban residents in 2014 (and covers 95% of total urban and rural residents in
China). The local government maintains identical electronic clinical information on all health
care provided to insured patients from the different provinces in China. In brief, we used the
medical insurance databases affiliated with the Chinese medical insurance scheme in Yunnan
Province, China, from January 1, 2001 through December 30, 2012.
The certified validated records provided by the hospitals were included into this
governmental medical insurance claims database. Every individual participating in the medical health
plan has a permanent and personal registration number, through which every medical ‘event’
could be identified, no matter whether the events happened in clinics and hospitals, and this
would be written in the electronic medical records. Data captured included information on
demography, diagnosis and treatment of various medical conditions.
Sampling method was reported in our previous study [
]. All subjects were continually entered
into the governmental medical insurance plan since 2001. The medical insurance data was
compiled in Oracle RDBMS, version 10g (Oracle Corporation, Redwood Shores, California,
USA). Structured Query Language (SQL) and systematic sampling using randomization blocks
enabled random sampling of the study population. To avoid the less comprehensive coverage
in the first several years of this Chinese medical insurance project, a sampling strategy
according to year strata was taken. A random five-percent sampling was performed among the
enrolled individuals biennially, according to 2001–2002, 2003–2004, 2005–2006, 2007–2008,
2009–2010, 2011–2012 to make the data representing the population into the medical
insurance project every two years. Thus, a total of 1,228,639 persons were selected, but after
excluding persons with incomplete data (n = 2611) and readmissions (n = 754,582), we identified
471,446 cases for analysis. Of this cohort, 425,901 without history of stroke were identified.
The incidences of ischaemic or haemorrhagic stroke were studied from 2002 to 2012. Over the
total follow-up of 1,895,447 person-years, there were 13274 incident ischaemic strokes and
2917 incident haemorrhagic strokes for the final analysis (S1 Fig).
The Medical Ethics Committee of PLA General Hospital has been approved by the China
Food and Drug Administration (CFDA) (Registry number: XZF20120145) and this ethics
committee approved the present study protocol (Approval number: 13BJZ40). The patient
records/information was anonymized and de-identified prior to analysis. The database in this
study was held by the government of Yunnan Province, China, which was managed with
Center for Medical Insurance, Human Resources and Social Security, Yunnan Province (http://
Evaluation of ischaemic stroke, haemorrhagic stroke and comorbidities
Ischaemic and haemorrhagic stroke (intracerebral and subarachnoid haemorrhage) were
defined as “a focal or global neurologic deficit of sudden onset, developing clinical symptoms
and/or signs, loss of cerebral function, with symptoms lasting more than 24 hours or leading to
death”, diagnosed clinically by a neurologist and confirmed by CT or MRI. Detailed clinical
information on ischaemic stroke, haemorrhagic stroke, and associated comorbidities were
based on ICD-9 and ICD-10 codes. The index date was the first date of diagnosis of ischaemic
or haemorrhagic stroke.
Ischaemic stroke cases were identified by International Classification of Disease, 9th Revision
[ICD-9] or International Classification of Disease, 10th Revision [ICD-10] codes 436 or I63.
Haemorrhagic stroke cases were identified by ICD-9 or ICD-10 codes 430,431,432; I60.x, I61.x. Heart
failure(ICD-9 codes:428; ICD-10 codes: I42, I50, I110,J819), dilated cardiomyopathy (ICD-9
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codes:425.4; ICD-10 codes: I42.0), diabetes (ICD-9 codes:249–250; ICD-10 codes: E10-E14),
hypertension(ICD-9 codes:401–405; ICD-10 codes: I10-I15), coronary artery disease (ICD-9
codes:410–414; ICD-10 codes: I20-I25), myocardial infarction(ICD-9 codes:410; ICD-10 codes:
I21,I22), peripheral vascular disease(ICD-9 codes:440.2; ICD-10 codes: I65, I70-74), chronic
obstructive pulmonary disease(ICD-9 codes:490–496; ICD-10 codes: J42,J44.0–9), hyperlipidemia
(ICD-9 codes:272.4; ICD-10 codes: E78.0–3,E78.5), renal dysfunction(ICD-9 codes:585,586;
ICD10 codes: M1A.3), hyperthyroidism(ICD-9 codes:242; ICD-10 codes: E05),
hypothyroidism(ICD9 codes:244; ICD-10 codes: E03), rheumatic heart disease (ICD-9 codes:393–398; ICD-10 codes:
I05,I06,I07,I09.9). ICD-9, ICD-10 codes defined cardiovascular disease and other comorbidities
are shown in S1 Table. The definition of various comorbidities is summarized in S2 Table.
Data for first hospitalization for ischaemic and haemorrhagic strokes from 2002 to 2012
year were retrieved from the medical insurance databases. This study did not include data for
Continuous variables were tested for normality by the Kolmogorov-Smirnov test. Those with a
normal distribution are presented as a mean (standard deviation, SD) and analyzed using t test.
Data with a non-normal distribution are presented as median (inter-quartile range, IQR). The
comparison of discrete variables was performed using the chi-square test.
Incident ischaemic and haemorrhagic strokes (per 1000 person-years, 95% confidential
interval, CI) were calculated in this population during a 10-year period. The rates of ischaemic
and haemorrhagic stroke were calculated in relation to different age group categories (age <65
years, age 65–74 years, and age 75 years), and the relative rate ratio for ischaemic to
haemorrhagic stroke in the three age groups over time were compared.
A multivariate analysis was used to determine cardiovascular risk factors predicting the
occurrence of ischaemic and haemorrhagic stroke in the general populations, respectively.
Factors associated with stroke were included into the Cox hazard proportional models, including
age 65, sex, CAD, vascular disease, hypertension, diabetes mellitus, atrial fibrillation (AF),
heart failure(HF), and renal dysfunction. Hazard ratios (HR) of cardiovascular risk factors for
ischaemic and haemorrhagic stroke were estimated by a Cox proportional hazards model. A p
value <0.05 was considered as statistically significant. The 95% confidential interval (CI) were
calculated based on Poisson distribution. Statistical analysis was performed using IBM SPSS
Statistics version 21.0 (SPSS, Inc., Chicago, Illinois).
Ischaemic strokes in relation to age, between 2002±2012
Among 425,901 individuals without prior stroke (52.4% male, median age 54), there were
13274 (63.8% male, median age 69) incident ischaemic strokes between 2002 to 2012.
Hypertension, diabetes mellitus and CAD were the most comorbidities (Table 1).
Ischaemic stroke rates (per 1000 patient-years, 95% CI) were 6.99 (6.90–7.10) during the
10-year period. The rate of ischaemic stroke decreased between 2002–2007, then remained
broadly similar between 2008–2012.
The population with ischaemic stroke in 2012 was on average 7 years younger than those in
2002 (mean age, SD: 67.7, 11.1; vs 74.9, 9.4) (p<0.05). Compared to patients age<65, ischaemic
stroke incidences were higher in the elderly (age <65 years versus age 65 years: 3.64 (3.33–
4.00) and 14.33 (14.01–14.60), respectively, p<0.001) (Fig 1). When categorized as age <65
years, age 65–74 and age 75, ischaemic stroke incidences increased significantly in the very
elderly population during this 10-year period (p<0.001) (Fig 2).
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* COPD: Chronic obstructive pulmonary disease, ACE: Angiotensin converting enzyme; ARB: Angiotensin receptor blocker. The information of drug use
was collected on discharge.
Haemorrhagic strokes in relation to age, between 2002±2012
There were 2917 incident haemorrhagic strokes (67.8% male, median age 65) between 2002 to
2012, while the hypertension, vascular disease, and diabetes mellitus were the most
comorbidities (Table 1).
Haemorrhagic stroke rates (per 1000 patient-years, 95% CI) were 1.53 (1.50–1.60) within
the 10-year observational period. The rates of haemorrhagic stroke showed a decreasing
trend between 2002–2007, and remained approximately 1.3–1.9 from 2008–2012 (Fig 3).
There was a rise in antiplatelet therapy use between 2008 to 2012, ranged from 2.4% to 10.4%
The population with haemorrhagic stroke was on average 8 years younger in 2012,
compared to 2002 (mean age, SD: 62.8, 13.3; vs 71.0, 9.3) (both p<0.05). Compared to patients
age<65, haemorrhagic stroke incidences were higher in the elderly population (age <65 years
vs age 65 years: 1.09(1.00–1.10) and 2.52(2.40–2.70), respectively, p<0.001). There was no
significant difference in haemorrhagic stroke between the elderly and the very elderly
population (age 65–74 years vs age 75 years: 2.39 (2.21–2.60), 2.71(2.50–2.92), p = NS) (Fig 1). A
similar non-significant trend for haemorrhagic stroke between the elderly and the very elderly
population was seen throughout 10-year period (Fig 2).
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Fig 1. Rates of ischaemic stroke and hemorrhagic stroke in different age group.
The relative rate ratio of ischaemic to haemorrhagic stroke was 3.3 (3.64/1.09) in the
population age <65 years, increasing to 5.48 (13.10/2.39) and 5.93(16.08/2.71) in age 65–74 and age
75 categories, respectively (p<0.001) (Fig 1).
Drug therapies in relation to age
Compared to the population with haemorrhagic stroke, the population with ischaemic stroke
received more statins and antiplatelet therapy in all three age groups (all p <0.001) (Fig 4).
With ageing, the use of CCB, ACEI/ARB, statin and antiplatelet in population with ischaemic
Fig 2. Time trends of ischaemic and hemorrhagic stroke incidences in different age groups.
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Fig 3. Rates of ischaemic stroke and hemorrhagic stroke in 425901 Chinese from 2002 to 2012 year. Ischaemic stroke:
n = 13274; Hemorrhagic stroke: n = 2917.
stroke decreased (p for trend, <0.001), however, the trend was less evident with haemorrhagic
stroke (p for trend, NS) (Fig 4).
Fig 4. Drug therapies in patients with ischaemic and haemorrhagic stroke in relation to age groups. * Comparisons within the same age
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Ischaemic and haemorrhagic stroke shared common risk factors (age 65 years, CAD, vascular
disease, hypertension, diabetes mellitus and sex, all p <0.05), but the weights of these risk
factors were different. For example, age 65 contributed more to the ischaemic stroke than
haemorrhagic stroke (HR, (95%CI), 3.86 (3.72–4.00) for ischemic stroke; 2.88 (2.11–2.46) for
haemorrhagic stroke) (Table 2).
In subjects age<75 years, CAD (7.17, 4.14–12.37) and diabetes mellitus (3.27, 2.42–4.42)
contributed most to the developing of haemorrhagic stroke than ischaemic stroke (all
p<0.001). Amongst the very elderly, vascular disease (2.24, 1.49–3.37) was an additional major
risk factor of the haemorrhagic stroke, together with CAD and diabetes mellitus(all p<0.001)
In this study, our principal findings are as follows: (1) The rate of ischaemic stroke decreased
between 2002–2007, then remained broadly similar between 2008–2012, with a similar trend
for haemorrhagic stroke; (2) Compared to patients age<65, ischaemic and haemorrhagic
stroke incidences were higher in the elderly population, with no significant difference in
haemorrhagic stroke between the elderly and the very elderly population (age 65–74 versus age
75); and (3) Ischaemic and haemorrhagic stroke shared similar risk factors (age,
hypertension, CAD, vascular disease, and diabetes mellitus) in this Chinese population, but the relative
weights of risk factors were different.
* CAD: coronary artery disease, AF: atrial ®brillation. Sex: male.
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Ischaemic stroke (n = 13274)
Age 65 3.98
Vascular disease 1.81
Diabetes mellitus 1.22
Heart failure 1.28
Renal dysfunction 1.15
Haemorrhagic stroke (n = 2917)
Diabetes mellitus 3.11
Vascular disease 2.06
Age 65 2.33
Heart failure 0.96
Renal dysfunction 0.68
* CAD: coronary artery disease, AF: atrial ®brillation. Sex: male.
Among population age over 75 years in this cohort, there was no haemorrhagic strokes in the subjects with renal dysfunction (n = 284) and with AF
(n = 365).
The changing rates of ischaemic and haemorrhagic stroke were accompanied by a rise in
antiplatelet therapy use between 2008 to 2012. Whether this contributed to the decline of
stroke rates was uncertain, but increased public awareness and risk factor management, as well
as healthcare campaigns, including smoking cessation that could have improved outcomes
overall. Nonetheless, stroke rates are still higher than the reported rates in the Caucasian
population, confirming the heavy burden of stroke in China. Indeed, the reported stroke deaths in
China accounted for 29.4% of total stroke deaths in the world in 2010, although the
age-standardized stroke mortality has apparently reduced by 23.9% from 1990 to 2010 [
The global burden of stroke is increasing, but globally most of the burden of ischaemic and
haemorrhagic stroke is in developing countries, which bear 63% of incident ischaemic strokes
and 80% of haemorrhagic strokes [
]. In developing countries, the reported age-adjusted
incidence of stroke was 52 per 100000 person-years between 1970–1979 and 117 per 100000
person years in 2000–2008, compared to 63 to 94 per 100 000 person-years in developed countries
]. The age-adjusted incident first stroke (per 1000 person-years) was reported as 7.6, 6.2, and
5.3 in men, while was 6.2, 5.8, and 5.1 in women in 1950 to 1977, 1978 to 1989, and 1990 to
2004, respectively [
]. The incidence of ICH also decreased between 2000 to 2010, from an
annual incidence rate of 5.21/10 000 [95% CI, 4.36–6.24] to 4.30/10 000 [95% CI, 3.21–5.76])
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It is perhaps unsurprising that the risk of ischaemic and haemorrhagic stroke increased with
]. The cumulative effects of ageing on the cardiovascular risk factors over a
prolonged period would increase stroke risk [
]. However, the precise reasons for the
increasing relative rate ratio of ischaemic to haemorrhagic stroke with at age 65 in our population
are unclear, but could be impacted by the drug therapies. With ageing, for example, the use of
antihypertensive drugs (CCB, ACE/ARB), statin, and antiplatelet therapy use was reduced
amongst the population with ischaemic stroke. Of note, the rate ratio between age 75 years
and age 65–74 was broadly comparable. In the Fushimi AF Registry, the most elderly (age
85) patients also showed a higher incidence of stroke but similar major bleeding
(haemorrhagic stroke, etc.) risks compared with the “younger” AF population (age 75–84 years) [
the Loire Valley atrial fibrillation project, the relative risks of major bleeding also did not
increase amongst elderly patients with ageing [
]. The disability and mortality associated with
subtypes of stroke could also be related to ethnicity [
In this Chinese population, common cardiovascular risk factors such as age 65 years,
hypertension, CAD, diabetes mellitus, and vascular disease, all independently predicted the
risk for ischaemic and haemorrhagic stroke, broadly similar to that seen in Western
]. We have previously shown that the CHA2DS2-VASc scores (which is used as a
predictor of stroke in AF population), which clusters the common comorbidities, was
predictive of ischaemic stroke risk in this large Chinese population . The predictive ability of
CHA2DS2-VASc scores for stroke and thromboembolism has been confirmed in several
nonAF population studies [
Unsurprisingly, age-specific clinical risk factors for ischaemic and haemorrhagic stroke
could have ethnic differences [
]. In this present Chinese cohort, the average age of population
with ischaemic and haemorrhagic stroke was 7 to 8 years younger between 2002 to 2012. The
high stroke burden generated by those age<75 years is evident [
]. Both the young and elderly
population share common cardiovascular risk factors, but the relative weights of these risk
factors could be different. In people age <75 years, CAD and diabetes mellitus contributed more
to the developing of haemorrhagic stroke than ischaemic stroke. Amongst the very elderly,
vascular disease was another major risk factor for haemorrhagic stroke, together with CAD and
diabetes mellitus. In another study, the younger Mexican American population (age 45–59
years) with ischaemic stroke was more likely to have hypertension and diabetes, but less AF
compared to non-Hispanic whites [
]. In the INTERSTROKE study, five risk factors were
also identified for the risk of ischaemic and intracerebral haemorrhagic stroke, including
hypertension, current smoking, abdominal obesity, diet, and physical activity [
when considering the common clinical cardiovascular risk factors for ischaemic and
haemorrhagic stroke, it may be difficult to differentially weigh the risks for ischaemic and
haemorrhagic stroke, especially in a population at high risk for both subtypes of stroke. Genetic testing or
new biomarkers may be promising future tools to risk stratify for stroke [
]. To take the
agerelated preventive strategy and to set up more sensitive tools to risk stratify for ischaemic and
haemorrhagic stroke could be helpful for reducing the global incidence of stroke.
The major limitation of this study pertains to the use of a medical Insurance administrative
dataset. The prevalence of risk factors reported was lower than the hospital-based data, with
possible under-reporting and coding errors. However, the high accuracy of ICD9, ICD10 for
stroke with administrative datasets have been demonstrated in previous studies [
consistency of diagnosis and ICD codes using Chinese Medical Insurance database has been
confirmed in our previous study . Although the diagnosis of stroke was confirmed by CT
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or MRI scanning, data on the severity and disability associated with subtypes of stroke was
lacking. Furthermore, there was no data on smoking which was a limitation of this medical
insurance dataset. Finally, we used the medical insurance databases affiliated with the Chinese
medical insurance scheme in Yunnan Province in the present study, which may have issues on
generalizability to across China and other Asian populations.
In this large Chinese cohort, there was an increased risk of ischaemic stroke compared to
haemorrhagic stroke with ageing, which could be associated with different relative weights of risk
factors, respectively. CAD and diabetes mellitus contributed more to the developing of
haemorrhagic stroke than ischaemic stroke in those age<75 years, whilst vascular disease was an
additional major risk factor contributing to haemorrhagic stroke in the very elderly. It
highlights the preventive strategy -related to age from ischaemic and haemorrhagic stroke.
S1 Fig. Flowing chart of study population.
S1 Table. Comorbidity ICD codes.
S2 Table. Definitions of comorbidities.
Conceptualization: YG GYHL.
Data curation: YG.
Formal analysis: YG GYHL.
Funding acquisition: YG.
Investigation: YG HW TT YT YW YC.
Methodology: YG GYHL.
Project administration: YG.
Supervision: YG GYHL YC.
Validation: YG GYHL.
Visualization: YG GYHL HW TT YT YW YC.
We gratefully thank Zhang Wei, Center for Medical Insurance, Human Resources and Social
Security, Yunnan Province, for data collection and processing.
Writing – original draft: YG GYHL HW TT YT YW YC.
Writing – review & editing: YG GYHL YC.
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