The effect of coagulation traits on the risk of retinal vein occlusion: a mendelian randomization study

doi:10.21203/rs.3.rs-4519232/v1

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The effect of coagulation traits on the risk of retinal vein occlusion: a mendelian randomization study

https://doi.org/10.21203/rs.3.rs-4519232/v1

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Introduction Retinal vein occlusion (RVO) is the leading cause of vision loss due to an obstruction in the retinal venous system. While RVO is often linked to thrombotic tendencies and coagulation abnormalities, the exact role of coagulation traits in its development is not fully understood. This study aims to investigate the potential causal relationship between coagulation traits and the risk of RVO by analyzing publicly available genome-wide association study (GWAS) summary statistics.

Materials and methods A two-sample Mendelian randomization (MR) analysis framework was employed to investigate the causal relationship between coagulation traits and the risk of RVO. Stringent quality control measures were applied to select appropriate instrumental variables strongly linked to exposure, such as coagulation factor III (FIII), coagulation factor V (FV), coagulation factor VIII (FVIII), coagulation factor XI (FXI), coagulation factor VII (FVII) and coagulation factor X (FX), as well as plasmin, platelet count, platelet crit (PCT), mean platelet volume (MPV), and platelet distribution width (PDW). The study utilized the FinnGen project RVO GWAS summary statistics cohort, consisting of 372 RVO cases and 182,573 controls. The analysis focused on 11 coagulation traits.

Results The research suggests that genetically predicted plasma levels of FIII, FVII, MPV, and PCT may be potentially causative for reducing the risk of RVO, and that levels of FVIII may be potentially causative for increasing the risk of RVO.

Conclusion Our MR analysis, utilizing GWAS data from a comprehensive population-based study, revealed a causal association between plasma levels of FFIII, FVII, FVIII, MPV, and PCT with the risk of RVO.

Health sciences/Diseases

Health sciences/Risk factors

Mendelian randomization

Retinal vein occlusion

Coagulation factor

Platelet parameter

Causal association

Risk

1. The influence of different coagulation factors on RVO risk remains unclear.

2. Platelet parameter is associated with the risk of RVO.

What this study adds

1. Our study is the first to report we first showed that higher levels of genetically predicted FVIII were significantly associated with an increased risk of RVO, whereas FIII, FVII, MPV and PCT were negatively associated.

How this study might affect research, practice or policy

1. This extensive study has significantly enhanced our understanding of the role of the coagulation cascade in the pathogenesis of RVO. These findings could have important implications for the development of preventive and diagnostic strategies for RVO.

2. The findings robustly support a causal association between FIII, FVII, FVIII, MPV, and PCT, and the risk of RVO. It would likely be a potential target for RVO therapy.

RVO represents a leading cause of severe vision impairment among retinal vascular disorders¹, with a uniform sex distribution worldwide². RVO frequently manifests abruptly, leading to painless vision loss in the affected eye. Vision impairment in these patients primarily results from macular edema, while additional vision-threatening complications include macular neovascularization and vitreous hemorrhages. RVO manifests in two types: central retinal vein occlusion (CRVO) originating from thrombosis within the central retinal vein (the primary outflow vessel of the eye), and branch retinal vein occlusion (BRVO) arising from thrombosis within a branch retinal vein^3,4. The prevalence of CRVO varies between 0.1% and 0.4%, whereas branch retinal vein occlusion (BRVO) occurs in 0.6–1.2% of the population^2,5,6.

The exact cause of RVO is not fully understood, but research suggests that individuals with systemic arteriosclerotic vascular disease are at an increased risk of developing RVO^7–12. Factors related to Virchow's triad, including vessel damage, stasis, and hypercoagulability, are commonly associated with RVO. Some studies indicate that thrombophilic factors may play a more significant role in RVO development in younger patients^13–15, while others have conflicting opinions on the relevance of coagulation disorders as risk factors for RVO^16,17. Various established risk factors, such as advanced age, hypertension, and hyperlipidemia, have been linked to the occurrence of RVO^18–26. However, conducting observational studies like case-control or prospective longitudinal studies can be challenging due to practical limitations, as the presence of these risk factors can influence the assessment of RVO risk based on coagulation characteristics. Further research is needed to better understand the underlying mechanisms and risk factors associated with RVO to improve prevention, diagnosis, and treatment strategies for this vision-threatening condition.

MR studies have become more common in research and use genetic variants linked to a risk factor as instrumental variables to evaluate causal effects or identify potential false associations that may result from reverse causation in disease outcomes observed in traditional observational studies^27,28. While observational studies have explored the relationship between coagulation profiles and RVO, establishing a definitive causal link between these profiles and the condition remains challenging. The presence of confounding factors in traditional observational studies presents a significant obstacle in accurately determining the specific causal role of various coagulation characteristics in the risk of developing RVO. By utilizing MR studies, researchers may be able to overcome some of the limitations associated with observational studies and provide more robust evidence regarding the relationship between coagulation profiles and RVO. This approach can help clarify the causal pathways involved in the development of RVO and potentially inform more effective preventive and treatment strategies for this vision-threatening condition.

MR can complement observational studies by applying genetic data to examine causal relationships between putative risk factors and disease²⁹. To the best of our knowledge, MR studies on the relationship between coagulation traits and RVO have not been performed to date. In this study, we performed MR analyses to assess the relationship between genetically predicted coagulation traits and RVO risk.

Study design

In this study, GWAS summary-level data from the IEU Open GWAS Project database were utilized to explore the causal relationships between coagulation traits and the risk of RVO. The two-sample MR approach was employed to estimate these associations based on summary-level data. Ethical approval was obtained for all original studies used in the MR analysis, which was conducted using publicly available GWAS summary statistics. Three key assumptions are essential for conducting an MR analysis effectively. Firstly, genetic variants must be strongly correlated with the variables to serve as instrumental variables. Secondly, these genetic variants should be independent of any confounders between RVO and the variables being studied. Lastly, the genetic variants should impact the risk of RVO solely through the variables being investigated. The study design, as illustrated in Fig. 1, involved the identification of seven coagulation factors and four platelet parameters using publicly available GWAS data. Subsequently, two-sample MR analyses were performed using summary-level GWAS data from independent FinnGen cohorts to assess the causal impact of coagulation traits on the susceptibility to RVO.

Genetic instrumental variable selection

To explore the causal relationships among coagulation factors, platelet parameters, and RVO, we utilized instrumental variables. We accessed the MR Base database (http://www.mrbase.org/)³⁰, which houses an extensive compilation of summary statistics from numerous GWASs. Our approach involved searching for GWASs of coagulation factors in European populations to identify genetic variants associated with these factors. From this curated list, we selected coagulation factor III (FIII), coagulation factor V (FV), coagulation factor VIII (FVIII), coagulation factor XI (FXI), coagulation factor VII (FVII), coagulation factor X (FX), plasmin, platelet count, platelet crit (PCT), mean platelet volume (MPV), and platelet distribution width (PDW) as the available genome-wide significant single nucleotide polymorphisms (SNPs)^31–36 (Table S1). In order to select eligible instrumental variables for each coagulation indicator, we implemented a stringent quality control procedure. To avoid bias due to strong linkage disequilibrium (LD), we chose SNPs with genome-wide significance (P < 5e − 6) associated with specific coagulation metrics as candidate instrumental variables, with an r² critical value of 0.001 and a window size of 10 Mb; of which the r² value of 0.01 and a window size of 10 Mb were chosen for FVIII to serve only. Additionally, to assess the presence of weak instrumental variable bias, we calculated F-statistics to measure the strength of instrumental variables. F-statistics larger than 10 indicate a low possibility of weak instrumental variable bias^37,38. (Table S1).

RVO outcome data

To explore the causal relationships between coagulation factors, platelet parameters, and RVO, we utilized instrumental variables. By accessing the MR Base database (http://www.mrbase.org/)³⁰, which hosts comprehensive summary statistics from multiple GWASs, we searched for GWASs of coagulation factors in European populations to identify genetic variants associated with these factors. From this list, we identified FIII, FV, FVII, FXI, FVIII, FX, plasmin, platelet count, PCT, MPV, and PDW as significant genome-wide single nucleotide polymorphisms (SNPs)^31–36. (Table S1). To select eligible instrumental variables for each coagulation indicator, we implemented stringent quality control procedures. To avoid bias resulting from strong linkage disequilibrium (LD), we chose SNPs with genome-wide significance (P < 5e − 6) associated with specific coagulation metrics as candidate instrumental variables, with an r2 threshold of 0.001 and a window size of 10 Mb. Furthermore, F-statistics were computed to assess the robustness of the instrumental variables. Results indicated that F-statistics exceeding 10 suggest a minimal risk of weak instrumental variable bias^37,38.(Table S1).

Summary-level data pertaining to RVO were extracted from the FinnGen study, consisting of 372 RVO cases and 182,573 controls³⁹.

Mendelian randomization estimates

We employed summary statistics, including β coefficients and standard errors, to separately estimate the causal relationships between seven coagulation factors and four platelet parameters with RVO, utilizing various MR methods. For the primary MR analysis evaluating the non-confounded causal association among coagulation factors, platelet parameters, and RVO, we utilized the inverse variance weighted approach. Figure 1 delineates the three pivotal assumptions essential for this method⁴⁰. Initially conducted in the FinnGen cohorts, the MR analyses employed three distinct methods: inverse variance weighting (IVW), weighted mean (WM), and MR-Egger regression, each based on different assumptions. The IVW method was used as the primary statistical model. Heterogeneity in causal estimates among instrumental variables indicated a potential violation of the assumptions underlying MR analysis⁴¹. To scrutinize this heterogeneity, we used the Cochran's Q test and assessed it via both the causal estimates of the fixed-effects IVW method and MR-Egger regression. A P-value less than 0.05 was considered indicative of significant heterogeneity. MR Egger regression was utilized to evaluate potential pleiotropic effects of instrumental variables. The intercept term in MR-Egger regression may indicate directional horizontal pleiotropy in the causal estimates.

Selection of instrumental variables

We conducted a systematic compilation of genome-wide significant SNPs associated with seven coagulation factors (FIII, FV, FVIII, FXI, FVII, FX, and plasmin) and four platelet parameters (platelet count, PCT, MPV, and PDW) from various GWAS results via extensive literature review to investigate their potential causal effects on the risk of RVO^31–36 (Table S1). These indicators were categorized into five distinct groups: platelet parameters (platelet count, PCT, MPV, and PDW), coagulation intrinsic pathway (FXI, FVIII), extrinsic pathway (FVII, FIII), common pathways (FV, FX), and fibrin clot dissociation (plasmin). To assess the strength of each instrumental variable, we calculated F-statistics for each instrument-exposure association. In our study, the F-statistics notably exceeded 10, indicating robustness and strength of these SNPs as instrumental variables (Table S1). This rigorous selection process ensured that the instrumental variables used in our analysis were reliable and suitable for assessing causal relationships between coagulation factors, platelet parameters, and the risk of RVO,

Causal effects of coagulation indicator on retinal vein occlusion

Utilizing GWAS summary statistics retrieved from the FinnGen study involving 372 cases and 182,573 controls, we conducted MR analyses to assess the causal impacts of seven coagulation factors and four platelet parameters on the risk of RVO. The resulting MR estimates obtained from various methods are presented in Table S2. Notably, the IVW method provided substantial evidence supporting a causal link between coagulation traits and the occurrence of RVO. Our findings indicate that genetically predicted levels of FIII and FVII are associated with a reduced risk of RVO [FIII: (Inverse variance weighted: OR = 0.577, 95% CI: 0.346–0.962, P = 3.3513×10 − 2 Fig. 2, Table S2, Figure S1; FVII: (Inverse variance weighted: OR = 0.742, 95% CI: 0.568–0.969, P = 2.84×10 − 2) Fig. 2, Table S2, Figure S1]. Additionally, we observed that genetically predicted MPV and PCT levels are causally linked to a decreased risk of RVO [MPV: (IVW: OR = 0.783, 95% CI: 0.621–0.987, P = 3.848×10 − 2; MR Egger: OR = 0.686, 95% CI: 0.475–0.989, P = 4.401×10 − 2) Fig. 3, Table S2, Figure S1]; PCT: (IVW: OR = 0.740, 95% CI: 0.560–0.977, P = 3.342×10 − 2; WM: OR = 0.590, 95% CI: 0.358–0.972, P = 3.821×10 − 2) Fig. 3, Table S2, Figure S1]. Intriguingly, our investigation identified a positive causal relationship between genetically predicted FVIII levels and RVO [IVW: OR = 1.308, 95% CI: 1.067–1.604, P = 9.787×10 − 3) Fig. 2, Table S2, Figure S1]. Nevertheless, no significant causal effect on RVO was observed for other coagulation factors (FV, FX, FXI, fibrinolytic enzymes) or platelet parameters (platelet count, PDW) (Fig. 2, Fig. 3, Table S2, Figure S1.). Additionally, the absence of significant horizontal pleiotropy or heterogeneity among coagulation factors and platelet parameters in our analyses strengthens the validity and reliability of the MR estimates obtained (Table S2). Leave-one-out analyses were conducted to identify any potential outliers, and Cochran's Q test indicated no influential individual SNP driving the IVW point estimate or causing heterogeneity between IVW estimates based on individual variants (Table S3, Figure S2). Both the funnel plot and MR Egger regression test showed no evidence of asymmetry, suggesting the absence of directional horizontal pleiotropy that could introduce bias to the MR analyses (Figure S3, Table S2). These results collectively contribute to our understanding of the causal relationships between coagulation traits and the risk of RVO.

Using summary statistics from GWAS of European ancestry, we examined the causal effects of seven coagulation factors and four platelet parameters on RVO risk by applying a unified MR framework for GWAS data analysis. Genetically forecasted plasma levels of FIII, FVII, MPV, and PCT demonstrated inverse correlations with RVO, while genetically anticipated plasma FVIII levels displayed a positive causal association with RVO.

RVO is a partial or complete blockage of a retinal vein in which the formation of a blood clot causes the retinal venous system to narrow and impedes venous return from the retinal circulation. The exact pathogenesis of RVO remains unclear. The condition may be due to a combination of three systemic changes known as Virchow’s triad: hemodynamic changes (venous stasis), degenerative changes of the vessel wall and blood hypercoagulability⁴². It has been shown to be associated with thrombotic events due to systemic changes, especially hypercoagulable states^3,41. The central retinal vein exits the eye at the optic disc and proceeds into the optic nerve. Within the optic nerve, it traverses through the lamina cribrosa, a connective tissue structure that offers support to the vein and the axons as they penetrate the sclera. Postmortem examination of eyes with CRVO revealed the presence of fresh or recanalized thrombus near the lamina cribrosa, where the vein typically narrows and blood flow intensifies³. BRVOs were observed at sites where arteries cross over veins, particularly those with an artery passing over a vein⁴³. In cases of BRVO, postmortem analysis showed thrombus formation within a retinal vein compressed by a thickened-walled retinal artery crossing over the vein⁴. Narrowing or irregularity of the vessels leads to turbulent flow and causes stress on endothelial cells^44,45.

Thrombophilia, arising from specific coagulation factor activation, has been implicated in the pathogenesis of thrombosis⁴⁶. Our study notably demonstrates a substantial correlation between genetically projected levels of FIII and FVII and a reduced RVO risk, representing the pioneering identification of a causal nexus between FIII, FVII, and RVO. The activation of the exogenous coagulation pathway begins with FIII, which is released to form a TF-Ca²⁺-FVII complex with FVII in the bloodstream thereby generating a cascade reaction to produce plasminogen activator, which generates thrombin. However, due to the action of procoagulants and anticoagulants, thrombin production by the FIII pathway becomes a threshold-limited process and the small amount of thrombin in the initial phase is insufficient to maintain the coagulation process⁴⁷. Despite the presence of a small amount of activated FVII in the blood, the coagulation process is similarly not initiated without the release of tissue factor. However, Hunter et al.'s prospective study, encompassing 18 central RVO and 22 branch RVO cases, did not discern a significant correlation between FVII and RVO⁴⁸. Nonetheless, our findings significantly contribute to understanding the potential association between coagulation factors and RVO risk.

High coagulation factor VIII activity is an independent risk factor for thromboembolism⁴⁹. Our findings are consistent with the observations in Glueck et al 's research, indicating elevated coagulation factor VIII levels in RVO or CRVO patients compared to controls^50,51. Moreover, Faude et al. corroborated the relationship between FVIII and RVO occurrence in their study involving 62 CRVO patients and 107 healthy individuals, with over 53.2% of CRVO patients exhibiting Factor VIII activity exceeding 150% (> 150 IU/dl) ⁵². These collective studies underscore the relevance of coagulation factors, particularly FIII, FVII, and FVIII, in the pathogenesis and risk assessment of RVO.

The findings regarding MPV in our study imply a possible adverse causal link with RVO, contradicting some observational studies and meta-analyses^53–57. Historically, studies employing traditional observational methods have generated inconsistent outcomes concerning the association between MPV and RVO. For instance, prior investigations have indicated a correlation between elevated MPV and RVO^53,58. Sahin et al.'s retrospective analysis involving 193 RVO patients and 83 healthy controls revealed significantly higher MPV values in the RVO patient group⁵⁴. Similarly, Yilmaz and Yilmaz reported a similar trend in another retrospective study⁵⁸. They suggested that larger platelets have greater haemostatic reactivity. However, Ornek et al. did not observe any association between increased MPV values and RVO occurrence⁵⁶. They concluded that the key factor in the development of RVO appears to be changes in the neighboring arteries rather than systemic haematological abnormalities. Moreover, within the cohort displaying clinical features of RVO, it was observed that patients diagnosed with BRVO had a lower MPV value compared to those suffering from central RVO and a control group⁵⁶. These studies exhibited considerable heterogeneity in terms of ethnicity, study design, participant numbers, participant characteristics, RVO identification, RVO prevalence, and statistical methodologies, potentially contributing to the discrepancies in findings. Past research has consistently identified age, hypertension, diabetes mellitus, and dyslipidemia as traditional risk factors for RVO^58–62. Some researchers postulate a greater significance of thrombophilia in younger patients^63–65. Study confounders could potentially bias the causal association between MPV and RVO. The inclusion of a small patient cohort might have influenced statistical significance. Notably, patient body mass index was not documented and considered, despite its potential impact on MPV values. Considering that most previous studies were traditional retrospective studies, the use of new research methods is particularly important for these clinical questions. Dual-sample MR analysis was applied to explore the risk factors for RVO. The exact mechanisms underlying the increased risk of low MPV and RVO have not been clarified. In in vitro experiments, smaller platelets secreted more P-selectin, which plays an important role in surface adhesion for thrombus formation⁶⁶. Smaller platelets with lower MPV were more likely to form thrombi than larger platelets⁶⁷. Notably, this result was observed in cancer patients. Therefore, the applicability of this finding to non-cancer patients remains to be confirmed. There are fewer studies and more basic research is needed in the future to explore the specific mechanisms. Furthermore, in the absence of a specific rationale for conducting a thorough hemostatic examination in patients with RVO, additional studies are required to elucidate the potential involvement of platelet parameters in the pathophysiology of RVO.

Our investigation has unveiled a association between PCT and RVO, a finding uncommon in current literature. There might exist a plausible negative causal link between platelet crit and RVO. Besides MPV, other indicators of platelet morphology, specifically PCT, could potentially wield substantial influence in vascular ailments, including atherosclerosis and thrombosis^68,69. However, findings from Yilmaz et al.'s study revealed no discernible difference in PCT levels between RVO patients and healthy controls⁵⁸. Further comprehensive research is essential to fully fathom the underlying mechanisms and mediators that dictate the relationship between PCT levels and RVO.

To our knowledge, this is the first study to evaluate MR studies that have assessed how different coagulation characteristics affect the risk of RVO, and the first to provide pooled estimates of the causal effects of FIII, FVII, FVIII, MPV and PCT on the risk of RVO. In addition, previous observational studies provided conflicting correlations and biological assumptions. By providing causality estimates, our study eliminates the true extent of the biological effects of relevant confounding risk factors on RVO.

Some potential limitation of our study should be mentioned. Firstly, in studies using sample-bank cohorts^31–36, causal effects represent only selected European populations. These were chosen primarily to avoid population stratification. However, these findings may not be representative of more general or non-European populations. Secondly, although we utilized the largest available sample size and the most recent GWAS dataset for MR analysis, it's essential to acknowledge that our study had a comparatively smaller sample size and event count compared to population-based observational studies. In addition, the inclusion of different studies using overlapping cohorts (especially databases), while unavoidable, inevitably reduces the effective sample size and statistical power of our analyses. Thirdly, we did not evaluate genetically predicted coagulation factors and platelet parameters in relation to CRVO and BRVO because of the lack of pooled data on CRVO and the inability to further subdivide MR analyses by other factors such as disease staging, further clinical trials are needed to confirm our findings in order to obtain partially consistent evidence of an association between certain coagulation characteristics and RVO or RVO of varying severity. In addition, our magnetic resonance study demonstrated a causal relationship between genetically predicted coagulation characteristics and RVO; however, it is important to note that the results of the magnetic resonance analyses were based on genetic evidence only.

Platelet play a pivotal role in thrombo-occlusive disorders, with MPV serving as a vital indicator of platelet size and activity. Larger platelets exhibit heightened reactivity, increased thromboxane A2 production, elevated expression of glycoprotein Ib and glycoprotein IIb/IIIa receptors, and a greater propensity for aggregation^70,71. The etiology of hypercoagulable states in RVO remains uncertain, lacking robust validation for extensive screening of thrombotic and coagulopathic conditions in most patients. However, assessing underlying coagulopathies might be warranted when routine tests for common cardiovascular risk factors yield negative results. These investigations should delve into the effects of various coagulation factors and platelet function on RVO, utilizing MR studies with more extensive sample sizes. Furthermore, conducting RVO MR studies among GWAS cohorts of diverse ethnicities will elucidate how distinct genetic compositions and diverse environments from inter-ethnic diversity influence the causal implications of specific coagulation profile-related risk factors in RVO development.

This study represents the pioneering use of MR to investigate the causal link between coagulation traits and RVO susceptibility specifically in a European population. The robust findings support a causal relationship between FIII, FVII, FVIII, MPV, PCT, and RVO risk. This comprehensive exploration significantly enhances our understanding of the coagulation cascade's involvement in RVO pathogenesis, potentially informing preventive and diagnostic strategies for RVO.

GWAS Genome-wide association study

IVW Inverse variance weighting

SNP Single nucleotide polymorphism

WM Weighted mean

MR Mendelian randomization

OR Odds ratio

MPV mean platelet volume

PDW platelet distribution width

PCT platelet crit

RVO retinal vein occlusion

Ethics statement

This MR study, which exclusively utilized publicly available summary statistics, was exempt from ethical approval.

Patient and Public Involvement
It was not appropriate or possible to involve patients or the public in the design, or conduct, or reporting, or dissemination plans of our research.

Conflict of interest

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Author details

1、Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, 130041, Jilin Province, China

2、Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266555, Shandong Province, China

Funding

Not applicable.

Author Contribution

Y. C.Y，Q .H and H. C performed conceived and designed the study. Q. H supervised the study and data analysis. Y.C.Y performed the data analysis with help from Q.H, Z.L, H. C and L.B.X. Q. H and Z. L and H.C supervised and revised the manuscript; all authors gave final approval for the submitted version of the manuscript.

Data Availability

We analyzed publicly available datasets which can be found here: The IEU Open GWAS Project database (https://gwas.mrcieu.ac.uk/).

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The effect of coagulation traits on the risk of retinal vein occlusion: a mendelian randomization study

Status:

Version 1

Abstract

Figures

What is already known on this topic

Introduction

Materials and methods

Study design

Genetic instrumental variable selection

RVO outcome data

Mendelian randomization estimates

Results

Selection of instrumental variables

Causal effects of coagulation indicator on retinal vein occlusion

Discussion

Conclusions

Abbreviations

Declarations

Ethics statement

Patient and Public Involvement
It was not appropriate or possible to involve patients or the public in the design, or conduct, or reporting, or dissemination plans of our research.

Conflict of interest

Author details

Funding

Author Contribution

Data Availability

References

Additional Declarations

Supplementary Files

Status:

Version 1

The effect of coagulation traits on the risk of retinal vein occlusion: a mendelian randomization study

Status:

Version 1

Abstract

Figures

What is already known on this topic

Introduction

Materials and methods

Study design

Genetic instrumental variable selection

RVO outcome data

Mendelian randomization estimates

Results

Selection of instrumental variables

Causal effects of coagulation indicator on retinal vein occlusion

Discussion

Conclusions

Abbreviations

Declarations

Ethics statement

Patient and Public Involvement It was not appropriate or possible to involve patients or the public in the design, or conduct, or reporting, or dissemination plans of our research.

Conflict of interest

Author details

Funding

Author Contribution

Data Availability

References

Additional Declarations

Supplementary Files

Status:

Version 1

Patient and Public Involvement
It was not appropriate or possible to involve patients or the public in the design, or conduct, or reporting, or dissemination plans of our research.