Hepatitis B virus infection won’t increase the risk of osteoporosis: Evidence from a mendelian randomization study in East Asian and European population

Hepatitis B virus infection won’t increase the risk of osteoporosis: Evidence from a mendelian randomization study in East Asian and European population | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 5 June 2025 V1 Latest version Share on Hepatitis B virus infection won’t increase the risk of osteoporosis: Evidence from a mendelian randomization study in East Asian and European population Authors : Jian-Qiang Chen 0009-0009-8260-5575 , Cheng-You Du , Xing-Yu Chen , and Wen-Tao Li [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174911236.62438520/v1 185 views 139 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background: Earlier observational researches have shown a relationship between hepatic B virus (HBV) infection and osteoporosis. Nonetheless, it is still uncertain whether these connections are due to direct causation or if they are influenced by other confounding factors. Objectives: To explore whether HBV infection will increase the risk of osteoporosis in East Asian and European population by the way of two-sample mendelian randomization (MR) analysis. Method: The HBV infection was utilized as the exposure variable and the osteoporosis was outcome variable. The Genome-wide association study (GWAS) data of the exposure and outcome variable were sourced from the website of IEU open GWAS project. A two-sample MR method was employed to examine the causal relationships, utilizing the inverse variance-weighted (IVW) as the primary analytical method. The sensitivity analysis was performed to evaluate the reliability of the results from the Mendelian randomization analysis. Result: The result of IVW indicated that patients with HBV infection wouldn’t increase the risk of osteoporosis in East Asian population (OR=1.042, 95%CI: 1.000-1.086, p=0.057) and in European population (OR=0.974, 95%CI: 0.832-1.074, p=0.691). The sensitivity analysis showed no evidence of heterogeneity or pleiotropy in this MR analysis. Conclusion: This two-sample MR analysis support that patients with hepatitis B virus infection won’t increase the risk of osteoporosis among East Asian and European population. Hepatitis B virus infection won’t increase the risk of osteoporosis: Evidence from a mendelian randomization study in East Asian and European population Jian-Qiang Chen 1 , Cheng-You Du 2 , Xing-Yu Chen 3 , Wen-Tao Li 4 1, 4 Department of Hepatobiliary Surgery, Chengdu Sixth People’s Hospital, Chengdu, Sichuan province, China. 2, 3 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China Correspondence: Wen-Tao Li, Email: [email protected] Abstract Background: Earlier observational researches have shown a relationship between hepatic B virus (HBV) infection and osteoporosis. Nonetheless, it is still uncertain whether these connections are due to direct causation or if they are influenced by other confounding factors. Objectives: To explore whether HBV infection will increase the risk of osteoporosis in East Asian and European population by the way of two-sample mendelian randomization (MR) analysis. Method: The HBV infection was utilized as the exposure variable and the osteoporosis was outcome variable. The Genome-wide association study (GWAS) data of the exposure and outcome variable were sourced from the website of IEU open GWAS project. A two-sample MR method was employed to examine the causal relationships, utilizing the inverse variance-weighted (IVW) as the primary analytical method. The sensitivity analysis was performed to evaluate the reliability of the results from the Mendelian randomization analysis. Result: The result of IVW indicated that patients with HBV infection wouldn’t increase the risk of osteoporosis in East Asian population (OR=1.042, 95%CI: 1.000-1.086, p=0.057) and in European population (OR=0.974, 95%CI: 0.832-1.074, p=0.691). The sensitivity analysis showed no evidence of heterogeneity or pleiotropy in this MR analysis. Conclusion: This two-sample MR analysis support that patients with hepatitis B virus infection won’t increase the risk of osteoporosis among East Asian and European population. Keywords: hepatitis B virus, mendelian randomization analysis, osteoporosis, causality, GWAS 1 Introduction Chronic hepatitis B virus (HBV) infection, a condition that affects approximately 257 million people worldwide, can lead to cirrhosis, hepatocellular carcinoma, hepatic failure, and premature death.[1] Osteoporosis is defined by a decrease in bone mass, without changes in bone composition, resulting in an increased likelihood of fractures.[2] Furthermore, osteoporosis is listed as the 5th highest in health care expenditure for age-related diseases, coming after diabetes mellitus, heart diseases, hypertension, and hyperlipidemia.[3] Over the past several years, some studies have suggested a link between HBV infection and osteoporosis, as most observational studies have shown that HBV infection raises the risk of osteoporosis.[4-6] Up to now, there aren’t randomized controlled trials (RCTs) exploring the relationship between HBV infection and osteoporosis. However, because of the strict approval of ethnics committee, it’s pretty difficult to perform a randomized controlled trial to validate whether HBV infection can increase the risk of osteoporosis. Besides, traditional observational studies are limited by confounding variables, which makes it challenging to determine a causal relationship between HBV infection and osteoporosis. Mendelian randomization (MR) serves as an epidemiological tool that examines the relationship between genetic variants strongly linked to an exposure of the research (such as anthropometric traits, behaviors, gene expression, or circulating metabolites) and specific outcomes (such as disease risk or mortality); i.e., evaluating whether these variants are associated with specific outcomes. Since genetic variants are naturally and randomly assigned at conception (during meiosis) and can now be measured on a large-scale analysis, the level of evidence of MR is pretty high. Benoit J. Arsenault established a hierarchy of scientific evidence pyramid about MR, which indicates the level of evidence of MR is higher than prospective cohort studies but lower than RCTs.[7] Therefore, given the lack of RCTs exploring the relationship between HBV infection and osteoporosis, this study utilizes MR methods to examine whether HBV infection can increase the risk of osteoporosis. 2 Methods 2.1 Study design The MR study was conducted based on three assumptions: 1) The genetic variants are robustly associated with HBV infection; 2) The genetic variants are not related to confounders; 3) The genetic variants influence osteoporosis solely by affecting HBV infection, rather than through other mechanisms.[8] Firstly, the Genome-wide association studies (GWAS) data including the exposure and outcome of Asian and European population was obtained from the IEU open GWAS project. The HBV infection population was assigned as exposure, and the osteoporosis population was assigned as outcome. Then, the two-sample MR study was performed to explore whether the exposure can increase the risk of outcome. 2.2 Data sources The GWAS summary data of East Asian population were obtained from BioBank Japan (BBJ) for both HBV infection and osteoporosis. The GWAS summary data of HBV infection was collected from 1394 cases and 211059 controls of Japanese descent, and the GWAS summary data of osteoporosis was obtained from a study involving 7788 cases and 204665 controls of Japanese descent.[9] The summary data of HBV infection from the GWAS for the European population was sourced from UK Biobank (UKB). The GWAS summary data regarding HBV infection was gathered from 145 cases and 351740 controls of European ancestry. The GWAS summary data for osteoporosis was collected from a study that included 3203 cases and 209575 controls of European ancestry. 2.3 Instrumental variable (IV) To establish a strong link with HBV infection, we chose SNPs that showed a significant association with HBV infection, having a p value of 5 ×\(10^{-8}\) to serve as instrumental variables (IVs). To eliminate linkage disequilibrium, we selected a clumping distance of 10000 kb and set an \(r^{2}\) threshold of less than 0.001. Besides, the \(R^{2}\)and F of each SNP was also computed to ensure the effectiveness and reliability of the IVs in the research. The F statistics were calculated using a formula: F= \(R^{2}\)(N − 2)/ (1 − \(R^{2}\)). In this formula,\(R^{2}\) represents the total explained variance in the chosen SNPs, while N denotes the sample size. \(R^{2}\) itself was determined using the equation: \(R^{2}\) = 2 × \(\beta^{2}\)× EAF × (1− EAF), where β stands for the estimated coefficient of the IV and EAF indicates the effect allele frequency. When F was greater than 10, there was enough strength to avoid weak instrument bias in the two-sample MR analysis. 2.4 Two-sample MR analysis The two-sample MR analysis was performed utilizing the ”TwoSampleMR” R package. The ”mr” function including five algorithms in the ”TwoSampleMR” was utilized to conduct the two-sample MR analysis, which contains MR Egger, Simple mode, Weighted mode, Weighted median, and Inverse variance weighted (IVW). Significantly, the outcome of the IVW method played a decisive role in determining the causal relationship between HBV infection and osteoporosis. Furthermore, the scatter plot, forest plot, and funnel plot were drawn to display the results of the MR analysis. Subsequently, a sensitivity analysis was conducted to assess the reliability of the aforementioned MR results by utilizing Heterogeneity, MR-PRESSO, Pleiotropy, and Leave-One-Out tests. Hereinto, Cochran’s Q test was conducted to detect the heterogeneity of the MR analysis 3 Results 3.1 Assessment prior to MR analysis In this MR analysis, 212453 of HBV infection and osteoporosis East Asian population were involved in total; 351885 of HBV infection European population and 212778 of osteoporosis European population were included in total. After the removal of linkage disequilibrium (LD) and screening of F-statistics, the HBV infection data and the osteoporosis data were harmonized. Following quality control, a total of 5 SNPs from the Asian population (details were shown in table 5) and 4 SNPs (details were shown in table 6) from the European population were chosen to represent HBV infection as IVs for the two-sample MR analysis between HBV infection and osteoporosis. Thereinto, the 5 SNPs from the Asian population included rs17191293, rs3763340, rs3134993, rs77746323 and rs72880511; the 4 SNPs from the European population included rs499606, rs114077552, rs114351943 and rs200365821. 3.2.1 MR analysis of HBV infection and osteoporosis in East Asian population This MR analysis using the inverse variance weighted (IVW) method revealed that the exposure factor of HBV infection wouldn’t increase the risk of the outcome factor of osteoporosis in people of East Asian descent (OR=1.042, 95%CI: 1.000-1.086, p=0.057), and the details were shown in table 1. Besides, the results of weighted median (WM) (OR=1.045, 95%CI: 0.993-1.100, p=0.089) and MR-Egger (OR=1.113, 95%CI: 0.946-1.310, p=0.287) were consistent with the result of IVW, which also indicated that HBV infection wouldn’t increase the risk of osteoporosis in people of East Asian descent (figure 2). 3.2.2 Sensitivity analysis of MR in East Asian population In this two-sample MR analysis, various statistical ways were employed for the sensitivity analysis. In order to validate the heterogeneity of this MR analysis among the IVs, the Cochran’s test was finished and the results indicated there wasn’t any heterogeneity (details were shown in table 3). Subsequently, the MR-PRESSO was carried out to detect whether there was an outlier, and the results showed there wasn’t any outliers. Additionally, the results of pleiotropy test demonstrated no significant horizontal pleiotropy bias (Egger intercept=-0.029, se=0.035, p=0.468). Furthermore, the forest plot (figure 3) and Leave-One-Out plot (figure 4) were drawn, and no outliers were found. The SNPs in the above MR analysis showed a symmetrical distribution in the funnel plot (figure 5), aligning with Mendel’s second law of random assortment. 3.3.1 MR analysis of HBV infection and osteoporosis in European population This MR analysis, which employed the IVW method, found that the exposure factor of HBV infection wouldn’t increase the risk of the outcome factor of osteoporosis among individuals of European population (OR=0.974, 95%CI: 0.832-1.074, p=0.691) (details were shown in table 2). Furthermore, the findings from the WM (OR=0.937, 95%CI: 0.803-1.0940, p=0.407) and MR-Egger (OR=1.107, 95%CI: 0.548-2.238, p=0.803) analyses aligned with those of the IVW, also indicating that HBV infection wouldn’t increase the risk of osteoporosis among individuals of European population (figure 6). 3.3.2 Sensitivity analysis of MR in European population After the MR analysis, different statistical methods were used for the sensitivity analysis. To assess the heterogeneity of this MR analysis among the IVs, Cochran’s test was conducted, and the results showed no evidence of heterogeneity (details are provided in table 4). Then, the MR-PRESSO analysis was conducted to identify whether there were any outliers, and the findings indicated that no outliers were present. Furthermore, the outcomes of the pleiotropy test showed no notable bias in horizontal pleiotropy (Egger intercept=-0.056, se=0.154, p=0.752). Additionally, the forest plot (figure 7) and the Leave-One-Out plot (figure 8) were created, and no outliers were identified. At last, the selected SNPs in the MR analysis presented a balanced distribution in the funnel plots (figure 9), which is consistent with Mendel’s second law of random assortment. 4 Discussion This is the first research to reach the conclusion that hepatitis B virus infection won’t increase the risk of osteoporosis by the way of two-sample MR analysis. The results of this study overturn the previous conclusion that hepatitis B virus infection increase the risk of developing subsequent osteoporosis. Overall, this MR analysis provides a genetic evidence to support the theory that hepatitis B virus infection does not elevate the risk of developing osteoporosis. In this MR analysis, 5 SNPs that were strongly associated with HBV infection of East Asian population were obtained from BBJ, and 4 SNPs that were strongly related to HBV infection of European population were sourced from UKB. The results of the two MR analysis indicated HBV infection didn’t increase the risk of osteoporosis both in East Asian population and in European population. In the past decades, some results of studies indicated there was a relationship between HBV infection and osteoporosis. Chen et al.[3] drew a conclusion that the patients with HBV infection exhibited a 1.14-fold (95% confidence interval [CI]: 1.03-1.25) higher risk of developing osteoporosis than patients without HBV infection, after they conducting a nationwide population-based cohort study in Taiwan. Peng et al.[6] hold the view that HBV infection might increase the risk of osteoporosis after carrying out a systemic review and meta-analysis. However, the result of a retrospective cohort study conducted by Lee et al.[10] indicated that patients with or without HBV infection showed similar risks of osteoporosis. Overall, there wasn’t a randomized controlled study or high-quality meta-analysis that could prove whether there was a relationship between HBV infection and the developing of osteoporosis up to now. This study provided a new genetic evidence confirming that patients with HBV infection wouldn’t have a higher risk of developing osteoporosis than patients without HBV infection. The reason why some results of studies indicated HBV infection was a risk factor for the developing of osteoporosis might be that the potential confounders influenced these studies such as medication use, demographic characteristics, comorbidities. Besides, the results of the observational study conducted by Chen et al. indicated the influence of HBV infection on osteoporosis as a risk factor isn’t so great, because the value of hazard ratio (HR) is only 1.14. All in all, these published studies couldn’t prove that HBV infection would improve the risk of developing osteoporosis. There are several strengths in this study. Firstly, this is the first study to demonstrate that HBV infection does not elevate the risk of developing osteoporosis based on a two-sample MR analysis. Secondly, this study provides genetic evidence of the relationship between HBV infection and osteoporosis based on East Asian and European population respectively. Therefore, the conclusion is not only applicable to East Asian population, but also is applicable to European population. Thirdly, we used various analytical methods and achieved consistent findings, which were confirmed through sensitivity analyses. Fourthly, the sample sizes of the two MR analysis included more than 200000 East Asian and European population respectively, and were much greater than previous observational studies. This larger sample size could offer sufficient statistical power to evaluate causality effectively. However, there are several limitations in this study. Firstly, despite employing various methods to examine pleiotropy, we could not entirely eliminate the possibility of pleiotropic effects. However, it is worth mentioning that various analytical methods yielded consistent outcomes that there wasn’t any pleiotropy. Secondly, there are a limited number of HBV infection-related IVs, which could affect the outcomes of the two-sample MR analysis. Hence, a MR analysis containing more IVs is essential to be performed to explore the relationship between HBV infection and osteoporosis. Thirdly, we only explored the influence of HBV infection on osteoporosis based on East population and European population respectively, so the conclusion might not be applicable to African population or American population. Consequently, further research involving different populations is needed to investigate the impact of HBV infection on osteoporosis. Fourthly, the existing GWAS summary data does not allow us to conduct a stratified analysis for further study. Consequently, we cannot stratify causal effects based on covariates such as age, sex, which may limit the scope of application of conclusion in this study. 5 Conclusion The results of the study indicate hepatitis B virus infection won’t increase the risk of osteoporosis among East Asian and European population from the genetic perspective. This finding provides a new and valuable viewpoint about the relationship between HBV infection and osteoporosis. Nonetheless, further studies are needed to validate our findings in different populations and to clarify the mechanisms. Conflicts of Interest The authors declared no potential conflicts of interest. Author’s contributions Jian-Qiang Chen designed the study; Xing-Yu Chen and Jian-Qiang Chen collected and analyzed the data; Jian-Qiang Chen wrote the manuscript; Wen-Tao Li corrected the manuscript; Cheng-You Du and Wen-Tao Li offered suggestions about improving the study. Acknowledgements The authors would like to express our gratitude to BioBank Japan (BBJ), UK Biobank (UKB) and IEU open GWAS project. Besides, the authors want to thank the researchers and consortiums for their generous contribution of the primary data. Data availability The GWAS summary statistics utilized in this research were sourced from the website of IEU open GWAS project (https://gwas.mrcieu.ac.uk). The summary statistics utilized in this research are anonymized, accessible for free download, and can be used without any limitations. reference 1 Wei MT, Le AK, Chang MS, Hsu H, Nguyen P, Zhang JQ, Wong C, Wong C, Cheung R, Nguyen MH. Antiviral therapy and the development of osteopenia/osteoporosis among Asians with chronic hepatitis B. J Med Virol 2019; 91 (7): 1288-1294 [PMID: 30776311 DOI: 10.1002/jmv.25433]2 Xie X, Huang R, Li X, Li N, Zhang H, Xu S, Li D, Xi S, Yang K. Association between hepatitis B virus infection and risk of osteoporosis: a systematic review and meta-analysis: A protocol for systematic review. Medicine (Baltimore) 2020; 99 (16): e19719 [PMID: 32311959 PMCID: PMC7220488 DOI: 10.1097/MD.0000000000019719]3 Chen CH, Lin CL, Kao CH. Association Between Chronic Hepatitis B Virus Infection and Risk of Osteoporosis: A Nationwide Population-Based Study. 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Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases. Nat Genet 2020; 52 (7): 669-679 [PMID: 32514122 PMCID: PMC7968075 DOI: 10.1038/s41588-020-0640-3]10 Lee HW, Kwon S, Moon YR, Ahn H, Lee J, Ahn SH. Incidence of Osteopenia or Osteoporosis in Asian Patients With Chronic Hepatitis B. J Gastroenterol Hepatol 2025 [PMID: 40312835 DOI: 10.1111/jgh.16982] Supplementary Material File (figure.docx) Download 105.99 KB File (table.docx) Download 23.46 KB Information & Authors Information Version history V1 Version 1 05 June 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords genetics hepatitis b virus hepatitis virus virus classification Authors Affiliations Jian-Qiang Chen 0009-0009-8260-5575 Sixth People's Hospital of Chengdu View all articles by this author Cheng-You Du The First Affiliated Hospital of Chongqing Medical University View all articles by this author Xing-Yu Chen The First Affiliated Hospital of Chongqing Medical University View all articles by this author Wen-Tao Li [email protected] Sixth People's Hospital of Chengdu View all articles by this author Metrics & Citations Metrics Article Usage 185 views 139 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Jian-Qiang Chen, Cheng-You Du, Xing-Yu Chen, et al. Hepatitis B virus infection won’t increase the risk of osteoporosis: Evidence from a mendelian randomization study in East Asian and European population. Authorea . 05 June 2025. 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