Effects of Hyperthyroidism on Venous Thromboembolism: A Mendelian Randomization Study

Han, Fushi; Zhang, Chunyang; Xuan, Miao; Xie, Zhuangli; Zhang, Kunming; Li, Ying

doi:https://doi.org/10.1155/2022/2339678

Journal of Immunology Research

On this page

Abstract Introduction Materials and Methods Results Discussion Conclusion Abbreviations Data Availability Conflicts of Interest References Copyright Related Articles

Special Issue

Extracellular Matrix and Immune Niches in Human Disease 2022

View this Special Issue

Research Article | Open Access

Volume 2022 | Article ID 2339678 | https://doi.org/10.1155/2022/2339678

Effects of Hyperthyroidism on Venous Thromboembolism: A Mendelian Randomization Study

Fushi Han,¹Chunyang Zhang,²Miao Xuan,²Zhuangli Xie,²Kunming Zhang,³and Ying Li²

Academic Editor: Li Peng Hu

Received12 May 2022

Revised11 Sept 2022

Accepted19 Sept 2022

Published12 Oct 2022

Abstract

Objective. Observational studies show the correlation between thyroid dysfunction and risk of venous thromboembolism. However, the causal effects remain uncertain. Our study was conducted to evaluate whether thyroid function and dysfunction were causally linked to the risk of venous thromboembolism. Methods. Publicly available summary data of thyrotropin (TSH) and free thyroxine (FT4), hypothyroidism, and hyperthyroidism were obtained from the ThyroidOmics Consortium and the UK Biobank. With single nucleotide polymorphisms (SNPs) as instrumental variables, the casual effects of genetically predicted TSH and FT4 and hypo- and hyperthyroidism on venous thromboembolism outcome were estimated through Mendelian randomization analysis methods (inverse variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode). Cochran’s Q test was performed to evaluate the heterogeneity and horizontal pleiotropy. Results. Our study selected 15 FT4-, 36 TSH-, 3 hyperthyroidism-, and 79 hypothyroidism-associated SNPs as instrumental variables. The IVW analysis results showed that the odds ratio of venous thromboembolism for hyperthyroidism was 1.124 (95% confidence interval: 1.019-1.240; ), demonstrating the casual effect of hyperthyroidism not FT4, TSH, and hypothyroidism on venous thromboembolism. No heterogeneity or horizontal pleiotropy was observed according to Cochran’s Q test. Conclusion. Our Mendelian randomization analysis supports the causal effect of hypothyroidism on risk of venous thromboembolism. There is no evidence that genetically predicted TSH, FT4, and hypothyroidism have casual effects on venous thromboembolism. Future studies should be conducted to elucidate the underlying pathophysiological mechanisms.

1. Introduction

Venous thromboembolism, including deep vein thrombosis and pulmonary embolism, is a chronic disease that affects approximately 10 million individuals per year globally [1, 2]. The annual incidence of acute venous thromboembolism is 1-2 cases per 1000 people and is four times higher in high-income countries compared with low-income countries [3]. The diagnostic methods of venous thromboembolism consist of sequential examinations combining clinical probabilities, D-dimer test, and imaging assessments [4]. Venous thromboembolism therapy is aimed at preventing thrombus extension and embolism, cardiopulmonary failure, deaths, recurrence, and long-term complications [5]. Direct oral anticoagulants and thrombin inhibitor are the major treatment strategies in the management of venous thromboembolism [6]. Venous thromboembolism is a multifactorial illness induced by the interaction of multiple predisposing factors [4]. Observational studies have showed the correlation between thyroid dysfunction and risk of venous thromboembolism. A prospective cohort study showed that hyperthyroidism not hypothyroidism was associated with lower risk of recurrent venous thromboembolism among elderly patients [7]. A meta-analysis of cohort studies also showed that hyperthyroidism was a risk factor of venous thromboembolism [8]. However, in a retrospective study, increased risk of venous thromboembolism was observed among patients with hypothyroidism not hyperthyroidism [9]. Nevertheless, it remains unclear whether the above observed associations are causal, because observational studies could have selection bias, residual confounding, and reverse causality.

Mendelian randomization is a research method that uses genetic variation as an instrumental variable to establish a model to test the causal relationship between variable exposure factors and diseases [10, 11]. Single nucleotide polymorphism (SNP) loci discovered by genome-wide association study (GWAS) based on large samples provide a large number of genetic variation tool variables for Mendelian randomization analysis, which can effectively reduce the bias of causality estimates [12–14]. Mendelian randomization has been widely used in venous thromboembolism studies, revealing the intrinsic link between various phenotypes and venous thromboembolism [15–17]. For instance, a Mendelian randomization study showed that obesity is casually correlated with venous thromboembolism [18]. Another study found that taller height acts as a risk factor of venous thromboembolism [19]. Based on previous research, this study collected currently available GWAS data on thyroid function and dysfunction. The causal relationships of free thyroxine (FT4), thyrotropin (TSH), hyperthyroidism, and hypothyroidism with venous thromboembolism were assessed using two-sample Mendelian randomization, which might provide a basis for prevention and treatment of venous thromboembolism.

2. Materials and Methods

2.1. Summary Data and Study Population

Our study acquired publicly available genetic summary data from two large GWAS cohorts (the ThyroidOmics Consortium [20] and the UK Biobank [21]) (Table 1). GWAS summary data on FT4 and TSH were accessed from the ThyroidOmics Consortium, composed of 72,167 venous thromboembolism samples. Meanwhile, GWAS summary data on hyperthyroidism and hypothyroidism were obtained from the UK Biobank, comprising 337,159 venous thromboembolism samples.

2.2. Selection of Instrumental Variables

The screening criteria of FT4-, TSH-, hyperthyroidism-, and hypothyroidism-associated SNPs as instrumental variables were as follows: (i) ; (ii) linkage disequilibrium was removed ( and ).

2.3. Two-Sample Mendelian Randomization Estimates

Five two-sample Mendelian randomization analysis methods containing inverse variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode were applied for estimating the casual effects of FT4, TSH, hyperthyroidism, and hypothyroidism on risk of venous thromboembolism. Among the five approaches, IVW was the main Mendelian randomization analysis to evaluate the causal effects because this approach is stable and accurate when directional pleiotropy is absent. All results were displayed as odds ratio (OR) and 95% confidence interval (CI), and values < 0.05 were considered statistically significant. In addition, the results were visualized into forest and scatter plots of the relationships of FT4-, TSH-, hyperthyroidism-, and hypothyroidism-associated SNPs with risk of venous thromboembolism.

2.4. Heterogeneity and Pleiotropy Test

Mendelian randomization analysis exists heterogeneity because of the differences in platforms, experimental conditions, inclusion populations, and SNPs. Cochran’s Q test of IVW analysis was conducted to detect heterogeneity. values < 0.05 indicated significant heterogeneity.

2.5. Statistical Analysis

All statistical analysis was implemented utilizing Two-Sample MR package in R (version 3.6.2) [22].

3. Results

3.1. Selection of FT4-, TSH-, Hyperthyroidism-, and Hypothyroidism-Associated SNPs as IVs

This study was conducted to investigate the causal relationships of FT4, TSH, hyperthyroidism, and hypothyroidism with venous thromboembolism via adopting two-sample Mendelian randomization. Based on the ThyroidOmics Consortium, we identified SNPs associated with thyroid function (FT4 and TSH). According to , LD , and , we identified 15 FT4-associated SNPs as IVs, including rs10119187, rs10739496, rs10818937, rs10946313, rs11039355, rs113107469, rs17185536, rs2235544, rs225014, rs4149056, rs4842131, rs4954192, rs56069042, rs6785807, and rs9356988 (Table 2). Meanwhile, 36 TSH-associated SNPs were used as IVs, as follows: rs1042673, rs1045476, rs1079418, rs10814915, rs10917469, rs10957494, rs11159482, rs11255790, rs1157994, rs11732089, rs1203944, rs12284404, rs1265091, rs12893151, rs13015993, rs13329353, rs1663070, rs17020122, rs17477923, rs17767491, rs2127387, rs2439301, rs28502438, rs30227, rs334725, rs398745, rs4445669, rs4804413, rs4933466, rs59381142, rs7329958, rs8015085, rs9298749, rs9381266, rs9497965, and rs963384 (Table 3). Additionally, on the basis of UK Biobank, with the same criteria, we determined 3 hyperthyroidism-associated SNPs (rs2160215, rs28360997, and rs3087243; Table 4) as well as 79 hypothyroidism-associated SNPs as IVs (Table 5). As depicted in Figures 1(a)–1(d), forest plots displayed the estimates of each FT4-, TSH-, hyperthyroidism-, and hypothyroidism-associated SNP on venous thromboembolism.

(a)

(b)

(c)

(d)

Figure 1

Forest plots for the association of FSH-, TSH-, hyperthyroidism-, and hypothyroidism-associated SNPs with risk of venous thromboembolism. (a) FSH, (b) TSH, (c) hyperthyroidism, and (d) hypothyroidism. In the forest plots, black points represent the log OR for venous thromboembolism per SD increase in FSH, produced using each FSH-associated SNP as an IV. Red points represent the combined causal estimates using all SNPs as an IV on the basis of MR-Egger and IVW methods. Horizontal line represents 95% CI of the estimates. Abbreviations: SNP: single nucleotide polymorphism; TSH: thyrotropin; OR: odds ratio; CI: confidence interval.

3.2. Two-Sample Mendelian Randomization Analysis for Evaluating Causal Effects of FT4, TSH, Hyperthyroidism, and Hypothyroidism on Venous Thromboembolism

Five different two-sample Mendelian randomization analysis approaches (IVW, MR-Egger, weighted median, sample mode, and weighted mode) were conducted to assess the casual effects of FT4, TSH, hyperthyroidism, and hypothyroidism on risk of venous thromboembolism, as shown in Figures 2(a)–2(d). For the IVW analysis results, the OR of venous thromboembolism for hyperthyroidism was 1.124 (95% CI: 1.019-1.240; ), without statistical significance for the MR-Egger, weighted median, sample mode, and weighted mode analysis results (Table 6). Meanwhile, no statistical significance from the five Mendelian randomization analysis approaches was found for FT4, TSH, and hypothyroidism on venous thromboembolism. The above data demonstrated that hyperthyroidism was a risk factor of venous thromboembolism.

(a)

(b)

(c)

(d)

Figure 2

Scatter plots for the association of FSH-, TSH-, hyperthyroidism-, and hypothyroidism-associated SNPs with risk of venous thromboembolism. (a) FSH, (b) TSH, (c) hyperthyroidism, and (d) hypothyroidism. In the scatter plot, -axis represents SNP effects on FSH, TSH, hyperthyroidism, and hypothyroidism (SD), and -axis represents venous thromboembolism risk (log OR and 95% CI). The Mendelian randomization regression slopes of the lines denote the causal estimates utilizing five methods (IVW, MR-Egger, weighted median, simple mode, and weighted mode). Abbreviations: SNP: single nucleotide polymorphism; TSH: thyrotropin; OR: odds ratio; CI: confidence interval.

3.3. Heterogeneity and Pleiotropy Test

Through Cochran’s Q test of IVW, we evaluated the heterogeneity and horizontal pleiotropy. A significant heterogeneity was found among FT4-associated SNPs on venous thromboembolism (). Moreover, there was no heterogeneity among TSH- (), hyperthyroidism- (), or hypothyroidism-associated SNPs () on venous thromboembolism (Table 7). Further analysis showed that FT4- (), TSH- (), hyperthyroidism- (), and hypothyroidism- () associated SNPs had no horizontal pleiotropy between FT4, TSH, hyperthyroidism, and hypothyroidism and risk of venous thromboembolism. As shown in funnel plots, when a single FT4-, TSH-, hyperthyroidism-, or hypothyroidism-associated SNP was used as an IV, the points representing the causality were relatively symmetrically distributed, suggesting that the cause was unlikely to be influenced by potential bias (Figures 3(a)–3(d)).

(a)

(b)

(c)

(d)

4. Discussion

Randomized controlled trials are the gold standard for causal inference in clinical research but are expensive and time-consuming and often difficult to implement due to ethical factors and subject constraints [23, 24]. Observational studies are relatively easy to implement and are widely applied for initial determination of etiology [25, 26]. Nonetheless, when there are reverse causal effects and potential confounding factors, the results of observational studies are often difficult to be recognized [27]. Mendelian randomization method provides an effective way to solve the above problems, using genetic variation as an instrumental variable effectively to avoid confounding factors caused by the environment [28]. Furthermore, compared with the immediate results obtained from randomized controlled trials, the exposure factors obtained from a genetic point of view are often accompanied for life and can even be passed on to the next generation [29]. Based on above evidence, we carried out the two-sample Mendelian randomization study to analyze the casual effects of FT4, TSH, hyperthyroidism, and hypothyroidism on venous thromboembolism.

The IVW method applies the ratio method to calculate causality estimates for individual instrumental variables and aggregates each estimate to perform a weighted linear regression to obtain an overall estimate [30]. However, this method cannot calculate the bias caused by pleiotropy, so an additional Cochran’s Q test is needed to evaluate pleiotropy [31]. Our IVW analysis results showed that the ORR of venous thromboembolism for hyperthyroidism was 1.124 (95% CI: 1.019-1.240; ), demonstrating the casual effect of hyperthyroidism not FT4, TSH, and hypothyroidism on venous thromboembolism. Additionally, there was no heterogeneity or horizontal pleiotropy in accordance with Cochran’s Q test. Genome-wide association analysis uncovers that most variations in thyroid function are genetically determined [20]. In a nationwide population-based cohort study, hypothyroidism was in relation to higher risk of venous thromboembolism [32]. Decreased venous thromboembolism risk of hypothyroid patients treated with thyroxine replacement therapy was not investigated. However, our Mendelian randomization analysis showed that there was no causal effect of thromboembolism on venous thromboembolism. Another cohort study showed that TSH levels within the normal range were not associated with venous thromboembolism risk, but abnormal TSH levels were associated with moderate risk of venous thromboembolism [33]. Case-control studies have shown the significant association between serum TSH levels and increased risk of venous thromboembolism [34]. Consistently, TSH concentration was an independent risk factor of venous thromboembolism regardless of thyroid function [35]. Our causal analysis demonstrated that TSH was not casually associated with venous thromboembolism.

However, there are several limitations in our study. Firstly, the sample sets included in this study are all from the European region. Whether the research conclusions can be extended to other populations still needs further research to be proven. Secondly, there may be population sharing of sample sets from Europe, leading to overuse of genetic information.

5. Conclusion

Altogether, in the two-sample Mendelian randomization study with genome-wide association variants, our evidence demonstrated that hypothyroidism was casually associated with venous thromboembolism outcome. However, there was no evidence that TSH, FT4, and hypothyroidism had casual effects on venous thromboembolism. Despite this, further studies are required to validate the biological mechanisms underlying the casual association.

Abbreviations

SNP:	Single nucleotide polymorphism
GWAS:	Genome-wide association study
FT4:	Free thyroxine
TSH:	Thyrotropin
IVW:	Inverse variance weighted
OR:	Odds ratio
CI:	Confidence interval.

Data Availability

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Conflicts of Interest

The authors declare no conflicts of interest.

References

M. E. Colling, B. E. Tourdot, and Y. Kanthi, “Inflammation, infection and venous thromboembolism,” Circulation Research, vol. 128, no. 12, pp. 2017–2036, 2021.
View at: Publisher Site | Google Scholar
F. Khan, T. Tritschler, S. R. Kahn, and M. A. Rodger, “Venous thromboembolism,” Lancet, vol. 398, no. 10294, pp. 64–77, 2021.
View at: Publisher Site | Google Scholar
D. M. Siegal, J. W. Eikelboom, S. F. Lee et al., “Variations in incidence of venous thromboembolism in low-, middle-, and high-income countries,” Cardiovascular Research, vol. 117, no. 2, pp. 576–584, 2021.
View at: Publisher Site | Google Scholar
G. H. Lyman, M. Carrier, C. Ay et al., “American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer,” Blood Advances, vol. 5, no. 4, pp. 927–974, 2021.
View at: Publisher Site | Google Scholar
M. B. Streiff, B. Holmstrom, D. Angelini et al., “Cancer-associated venous thromboembolic disease, version 2.2021, NCCN clinical practice guidelines in oncology,” Journal of the National Comprehensive Cancer Network, vol. 19, no. 10, pp. 1181–1201, 2021.
View at: Publisher Site | Google Scholar
M. Serhal and G. D. Barnes, “Venous thromboembolism: a clinician update,” Vascular Medicine, vol. 24, no. 2, pp. 122–131, 2019.
View at: Publisher Site | Google Scholar
D. Segna, M. Méan, A. Limacher et al., “Association between thyroid dysfunction and venous thromboembolism in the elderly: a prospective cohort study,” Journal of Thrombosis and Haemostasis, vol. 14, no. 4, pp. 685–694, 2016.
View at: Publisher Site | Google Scholar
S. Srisawat, T. Sitasuwan, and P. Ungprasert, “Increased risk of venous thromboembolism among patients with hyperthyroidism: a systematic review and meta-analysis of cohort studies,” European Journal of Internal Medicine, vol. 67, pp. 65–69, 2019.
View at: Publisher Site | Google Scholar
L. G. Danescu, A. Badshah, S. C. Danescu et al., “Venous thromboembolism in patients hospitalized with thyroid dysfunction,” Clinical and Applied Thrombosis/Hemostasis, vol. 15, no. 6, pp. 676–680, 2009.
View at: Publisher Site | Google Scholar
B. D. Pearce, “Mendelian randomization of cytokines in schizophrenia and depression: what does this tell us about causal chains in these illnesses?” Brain, Behavior, and Immunity, vol. 99, pp. 130-131, 2022.
View at: Publisher Site | Google Scholar
X. Liu, X. Tong, Y. Zou et al., “Mendelian randomization analyses support causal relationships between blood metabolites and the gut microbiome,” Nature Genetics, vol. 54, no. 1, pp. 52–61, 2022.
View at: Publisher Site | Google Scholar
S. Ai, J. Zhang, G. Zhao et al., “Causal associations of short and long sleep durations with 12 cardiovascular diseases: linear and nonlinear Mendelian randomization analyses in UK Biobank,” European Heart Journal, vol. 42, no. 34, pp. 3349–3357, 2021.
View at: Publisher Site | Google Scholar
N. Kappelmann, J. Arloth, M. K. Georgakis et al., “Dissecting the association between inflammation, metabolic dysregulation, and specific depressive symptoms: a genetic correlation and 2-sample Mendelian randomization study,” JAMA Psychiatry, vol. 78, no. 2, pp. 161–170, 2021.
View at: Publisher Site | Google Scholar
Y. Fu, F. Xu, L. Jiang et al., “Circulating vitamin C concentration and risk of cancers: a Mendelian randomization study,” BMC Medicine, vol. 19, no. 1, p. 171, 2021.
View at: Publisher Site | Google Scholar
M. Arvanitis, G. Qi, D. L. Bhatt et al., “Linear and nonlinear Mendelian randomization analyses of the association between diastolic blood pressure and cardiovascular events: the J-curve revisited,” Circulation, vol. 143, no. 9, pp. 895–906, 2021.
View at: Publisher Site | Google Scholar
J. Luo, S. le Cessie, D. van Heemst, and R. Noordam, “Diet-derived circulating antioxidants and risk of coronary heart disease: a Mendelian randomization study,” Journal of the American College of Cardiology, vol. 77, no. 1, pp. 45–54, 2021.
View at: Publisher Site | Google Scholar
Z. Zhuang, M. Gao, R. Yang, Z. Liu, W. Cao, and T. Huang, “Causal relationships between gut metabolites and Alzheimer's disease: a bidirectional Mendelian randomization study,” Neurobiology of Aging, vol. 100, pp. 119.e15–119.e18, 2021.
View at: Publisher Site | Google Scholar
S. Lindström, M. Germain, M. Crous-Bou et al., “Assessing the causal relationship between obesity and venous thromboembolism through a Mendelian randomization study,” Human Genetics, vol. 136, no. 7, pp. 897–902, 2017.
View at: Publisher Site | Google Scholar
N. S. Roetker, S. M. Armasu, J. S. Pankow et al., “Taller height as a risk factor for venous thromboembolism: a Mendelian randomization meta-analysis,” Journal of Thrombosis and Haemostasis, vol. 15, no. 7, pp. 1334–1343, 2017.
View at: Publisher Site | Google Scholar
R. Sterenborg, T. E. Galesloot, A. Teumer et al., “The effects of common genetic variation in 96 genes involved in thyroid hormone regulation on TSH and FT4 concentrations,” The Journal of Clinical Endocrinology and Metabolism, vol. 107, no. 6, pp. e2276–e2283, 2022.
View at: Publisher Site | Google Scholar
N. Rusk and U. K. The, “The UK Biobank,” Nature Methods, vol. 15, no. 12, p. 1001, 2018.
View at: Publisher Site | Google Scholar
G. Hemani, J. Zheng, B. Elsworth et al., “The MR-Base platform supports systematic causal inference across the human phenome,” eLife, vol. 7, 2018.
View at: Publisher Site | Google Scholar
W. Zhou, G. Liu, R. J. Hung et al., “Causal relationships between body mass index, smoking and lung cancer: univariable and multivariable Mendelian randomization,” International Journal of Cancer, vol. 148, no. 5, pp. 1077–1086, 2021.
View at: Publisher Site | Google Scholar
S. E. Baumeister, H. Baurecht, M. Nolde et al., “Cannabis use, pulmonary function, and lung cancer susceptibility: a Mendelian randomization study,” Journal of Thoracic Oncology, vol. 16, no. 7, pp. 1127–1135, 2021.
View at: Publisher Site | Google Scholar
X. Zhu, T. Li, X. Niu, L. Chen, and C. Ge, “Identification of UBE2T as an independent prognostic biomarker for gallbladder cancer,” Oncology Letters, vol. 20, no. 6, p. 1, 2020.
View at: Publisher Site | Google Scholar
X. Niu, B. Huang, J. Yang et al., “Odontogenic carcinosarcoma with dentinoid: a rare case report,” The Journal of International Medical Research, vol. 49, no. 9, 2021.
View at: Publisher Site | Google Scholar
W. Sproviero, L. Winchester, D. Newby et al., “High blood pressure and risk of dementia: a two-sample Mendelian randomization study in the UK Biobank,” Biological Psychiatry, vol. 89, no. 8, pp. 817–824, 2021.
View at: Publisher Site | Google Scholar
J. S. Zheng, J. Luan, E. Sofianopoulou et al., “Plasma vitamin C and type 2 diabetes: genome-wide association study and Mendelian randomization analysis in European populations,” Diabetes Care, vol. 44, no. 1, pp. 98–106, 2021.
View at: Publisher Site | Google Scholar
A. Leong, J. B. Cole, L. N. Brenner, J. B. Meigs, J. C. Florez, and J. M. Mercader, “Cardiometabolic risk factors for COVID-19 susceptibility and severity: a Mendelian randomization analysis,” PLoS Medicine, vol. 18, no. 3, article e1003553, 2021.
View at: Publisher Site | Google Scholar
R. You, L. Chen, L. Xu et al., “High level of uromodulin increases the risk of hypertension: a Mendelian randomization study,” Frontiers in Cardiovascular Medicine, vol. 8, article 736001, 2021.
View at: Publisher Site | Google Scholar
C. J. Bull, J. A. Bell, N. Murphy et al., “Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study,” BMC Medicine, vol. 18, no. 1, p. 396, 2020.
View at: Publisher Site | Google Scholar
W. T. Wei, P. P. Liu, S. M. Lin et al., “Hypothyroidism and the risk of venous thromboembolism: a nationwide cohort study,” Thrombosis and Haemostasis, vol. 120, no. 3, pp. 505–514, 2020.
View at: Publisher Site | Google Scholar
G. Lerstad, K. F. Enga, R. Jorde et al., “Thyroid function, as assessed by TSH, and future risk of venous thromboembolism: the Tromsø study,” European Journal of Endocrinology, vol. 173, no. 1, pp. 83–90, 2015.
View at: Publisher Site | Google Scholar
J. Horacek, J. Maly, I. Svilias et al., “Prothrombotic changes due to an increase in thyroid hormone levels,” European Journal of Endocrinology, vol. 172, no. 5, pp. 537–542, 2015.
View at: Publisher Site | Google Scholar
M. Kovářová, T. Koller, V. Štvrtinová, and J. Payer, “Thyroid-stimulating hormone concentration as an independent risk factor of venous thromboembolism regardless of thyroid function,” Endokrynologia Polska, vol. 66, no. 6, pp. 474–479, 2015.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2022 Fushi Han et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

447

Downloads

601

Citations