Antidyslipidemia Pharmacotherapy in Chronic Kidney Disease: A Systematic Review and Bayesian Network Meta-Analysis

Background and Aims: The benefits and safety of antidyslipidemia pharmacotherapy in patients with chronic kidney disease were not well defined so the latest evidence was summarized by this work. Methods: This systematic review and Bayesian network meta-analysis (NMA) included searches of PubMed, Embase, and Cochrane Library from inception to 28 February 2022, for randomized controlled trials of any antilipidaemic medications administered to adults with chronic kidney disease [CKD: defined as estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73 m2 not undergoing transplantation], using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool to assess the certainty of the evidence. Results: 55 trials and 30 works of them were included in our systematic review and NMA, respectively. In comparisons with no antidyslipidemia therapy or placebo, proprotein convertase subtilisin/Kexin type 9 inhibitors plus statin (PS) was the most effective drug regimen for reducing all-cause mortality (OR 0.62, 95% CI [0.40, 0.93]; GRADE: moderate), followed by moderate-high intensity statin (HS, OR 0.76, 95% CI [0.60, 0.93]; I2 = 66.9%; GRADE: moderate). PS, HS, low-moderate statin (LS), ezetimibe plus statin (ES), and fibrates (F) significantly decreased the composite cardiovascular events. The subgroup analysis revealed the null effect of statins on death (OR 0.92, 95% CI [0.81, 1.04]) and composite cardiovascular events (OR 0.94, 95% CI [0.82, 1.07]) in dialysis patients. Conclusion: In nondialysis CKD patients, statin-based therapies could significantly and safely reduce all-cause death and major composite cardiovascular events despite the presence of arteriosclerotic cardiovascular disease and LDL-c levels. Aggressive medication regimens, PS and HS, appeared to be more effective, especially in patients with established CAD.


Introduction
With an estimated prevalence of 13.4% globally [1], chronic kidney disease (CKD) is currently a public health problem worldwide that imposes tremendous medical and financial burdens on society and healthcare systems. These patients have an absolute risk for cardiovascular events similar to that of persons with established coronary artery disease (CAD), and the risk increases linearly as the estimated glomerular filtration rate (eGFR) decreases below 60 mL/min/1.73 m 2 [2]. Given the elevated cardiovascular risk and evidence-based benefits of lipid management in general people, antidyslipidemia pharmacotherapy was assumed to be a reasonable way to improve clinical outcomes of CKD. However, unlike non-CKD populations, they frequently exhibit a characteristic lipid profile of hypertriglyceridemia but mostly normal or low LDL-c [3], and the benefit of

Data Sources and Searches
We searched the PubMed, Embase, and Cochrane Library databases from inception to 28 February 2022, with English as the language restriction. Clinical trial registries (www.clinicaltrials.gov, www.clinicaltrialsregister.eu, accessed on 29 February 2022), and references of the relevant articles, especially reviews, were also searched and reviewed to supplement the identified citations. Searches included terms relating to CKD, lipidlowering medication, and randomized controlled trials (RCTs; Supplementary Section S2, pp. 5-7). Three reviewers (LG, HK, and LX) used EndNote X9 (Clarivate Analytics, Philadelphia, PA, USA) to screen titles and abstracts, after which they read the full-text manuscripts and extracted data on study identifiers, study design and setting, participant characteristics at baseline, intervention, and outcomes. Discrepancies were resolved by discussion.

Study Selection
Eligible studies had to meet the following criteria: (1) RCTs irrespective of year of publication; (2) participants: adults aged ≥ 18 years old with CKD (defined as eGFR < 60 mL/min/1.73 m 2 ) regardless of comorbid clinically evident atherosclerosis and hyperlipidemia; (3) interventions: monotherapy or combination of any antidyslipidaemic pharmacotherapy and placebo/diet therapy; (4) outcomes: we deemed all-cause death as the critical outcome of interest; composite cardiovascular events (CV events, the definitions of the outcomes were taken as reported in the individual studies (Supplementary Sections S6.2.1 and S6.2.2, pp. [42][43][44][45] were the important but not critical outcomes; cardiovascular (CV) death, stroke, myocardial infarction (MI) and a reduction in LDL-c, safety outcomes including the change in eGFR and major drug-related adverse events (any muscle-related abnormalities, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≥2 times of upper limit) were deemed as less important outcomes. Subgroup analyses were planned to be performed in patients receiving dialysis therapy and with coronary artery disease. Only studies with at Pharmaceutics 2023, 15, 6 3 of 21 least a 3-month follow-up period were included, as those with a shorter duration would not allow the detection of significant changes in LDL-c. And only those with a follow-up duration ≥ 1 year can be included in the analysis of all-cause death and cardiovascular outcomes. To avoid minor study effects and generate more robust evidence, we selected studies enrolling at least 50 patients. In addition, we excluded trials for the following reasons: trials that used quasirandom methods; and studies enrolling mostly patients who underwent kidney transplants or were on the transplant waiting list. We have made some adjustments to the existing protocols: the medications included in this work finally were not limited to PCSK9i, statins, ezetimibe, and fibrates; we also explore the clinical outcomes of other hypolipidemic drugs by reviewing the RCTs related.

Data Extraction and Quality Assessment
Data extraction was performed independently by two authors (LG and WX) with a prespecified data extraction form incorporating information about studies, baseline characteristics of the participants, and outcomes-related data. We made efforts to contact the authors if the important data were not reported. The discrepancies were resolved by consensus or in consultation with a third reviewer (LY). The risk of bias assessment at the study level was performed by LG and WX independently using Rob2 [10], a revised Cochrane risk-of-bias tool for RCTs, with discrepancies resolved by LY. Then, we used the GRADE approach for entire networks, providing the framework for rating the certainty of the evidence of each paired comparison as high, moderate, low, or very low [11,12]. We also assess confidence in the results utilizing the Confidence-in-Network-Meta-Analysis (CINeMA) approach [13].

Data Synthesis and Analysis
The odds ratio (OR), the mean difference (MD), and their corresponding 95% confidence intervals (95% CI) were calculated for dichotomous outcomes and continuous outcomes with the random-effect model. Traditional pairwise meta-analysis by Review Manager 5.3 and network meta-analysis (NMA) with a Bayesian model through Markov chain Monte Carlo (MCMC) simulation by the R package GeMTC were carried out sequentially. The node-splitting method was applied to evaluate the inconsistency between direct and indirect comparisons. Inconsistency was deemed nonsignificant when the p-value was >0.05 for the comparison between direct and indirect effects. We quantified the proportion of variation in the meta-analyses due to clinical and methodological heterogeneity using I 2 (Higgins 2002), the value of which was classified as might not be important (0% to 40%), may represent substantial heterogeneity (30% to 60%) and considerable heterogeneity (75% to 100%). Convergence was assessed through visual inspection of the Brooks-Gelman-Rubin diagnostic, with convergence assumed to have occurred when the ratio of betweenand within-chain variability was stable at approximately one. Varying iterations and burn-in periods were used to ensure convergence, with burn-in periods discarded from the analysis. With Markov chain Monte Carlo (MCMC) modeling, the relative ranking probability of each treatment group was estimated, and then "Ranko grams" with the surface under the cumulative ranking curve (SUCRA) were reported to provide a comparative hierarchy of efficacy of the treatment groups. Prespecified subgroup analyses for patients with CKD and those receiving dialysis were performed. In addition, regression analysis and sensitivity analysis were performed to investigate the influence of serum LDL-c level and the presence of established arteriosclerotic cardiovascular disease on the results. Publication bias was assessed using a funnel diagram with Stata MP software version 15.0. To test the robustness of the results, we also conducted the analyses utilizing the frequentist method.

Description of Trials
Of the 6123 screened articles, 146 relevant full-text articles were selected after the removal of irrelevant trials, duplicate articles, reviews, protocols, and unavailable abstracts. After screening, 55 trials involving proprotein convertase subtilisin/Kexin type 9 inhibitors (PCSK9i), statins, ezetimibe, fibrates, bile acid sequestrants, niacin, and polyunsaturated fatty acids were finally included in our systematic review (Supplementary Section S1, p. 4). Given the practical clinical applications and the numbers of eligible RCTs, the NMA work included only the first 4 agents. Consequently, 30 works that included 45,627 patients and involved 5 medication regimens-PCSK9i under background use of a moderate-high intensity statin (PS), statins of low-moderate intensity (LS: <40 mg of atorvastatin) and moderate-high intensity (HS: 40-80 mg of atorvastatin or the highest dose patients could tolerant), the combination of ezetimibe and statin (ES) and fibrates (F)-were available for quantitative analyses . The definition of CKD differed among the studies, with most applying eGFR below 60 mL/min/1.73 m 2 as the criteria. Although a small number of studies enrolling some patients with a higher eGFR, we still included them as the majority of patients met our requirement. The average follow-up duration was 51.8 months. The inclusion criteria and major findings of all 55 studies are summarized and presented in the supplementary materials (Supplementary Section S4, pp. 8-27).

Patient Characteristics
The baseline characteristics of patients enrolled in the NMA are shown in Table 1. The cohorts consisted of 58.0% male patients, with an average age of 65.4 years. The frequently reported comorbid conditions were diabetes, hypertension, and arteriosclerotic cardiovascular disease, and other major medication treatments included but were not limited to antiplatelet medicines, antihypertensive agents such as angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs), beta-blockers and calcium channel blockers (CCBs). Where data were available, the baseline LDL-c, high-density lipoprotein cholesterol (HDL-c) and triglyceride (TG) levels were 3.0, 1.2, and 1.9 mmol/L, respectively. Only 3 trials studied the effects of statins in dialysis patients.

Risk of Bias in Individual Trials and the Grade of Evidence
The risk of bias at the study level is summarized in the supplemental file (Supplementary Section S5, pp. [28][29][30]. Eleven trials were at high risk of bias primarily because of performance and detection bias. Except for Stegmayr's study [37], the trials pooled to conduct the NMA were assessed as works of moderate-high quality. The details of evidence evaluation utilizing GRADE and CINeMA approach are both available in the supplementary materials (Supplementary Sections S7 and S8, pp. 62-74).

Risk of Bias in Individual Trials and the Grade of Evidence
The risk of bias at the study level is summarized in the supplemental file (Supplementary Section S5, pp. [28][29][30]. Eleven trials were at high risk of bias primarily because of performance and detection bias. Except for Stegmayr's study [37], the trials pooled to conduct the NMA were assessed as works of moderate-high quality. The details of evidence evaluation utilizing GRADE and CINeMA approach are both available in the supplementary materials (Supplementary Sections S7 and S8, pp. 62-74).

All-Cause Death
A total of 20 studies reported information about the effect of lipid-lowering therapies on all-cause mortality in CKD patients, and finally, the data of 18 studies that involved 41,213 individuals were available for NMA [16,[18][19][20][21][22][23]29,[33][34][35][36][37][38][40][41][42]44]. Network plots of available direct comparisons and the pooled odds ratios (OR) with 95% confidence intervals (95% CI) corresponding to the pairwise meta-analysis are shown in Figures 1A Figure 1E). According to the trials without a high risk of bias, the effects on LDL-c reduction of these regimens remained consistent with those in the general population.

Estimated Glomerular Filtration Rate
29 trials reported antilipidemic treatment effects on renal function, while we failed to perform a quantitative analysis, as few of them reported the renal outcome systematically. Studies of moderate-high quality revealed no significant association between the decrease in eGFR and the use of lipid-lowering treatment among CKD patients regardless of baseline renal function. on the contrary, they found that statin-based therapy improved the eGFR slightly or retarded its further decrease in the long-term follow-up [18,19,32,41,46]. Compared to LS, an aggressive antilipidemic method using HS augments the reno-protective property [18,19]. The combination of fenofibric acid and rosuvastatin was found to be associated with a reversible negative impact on eGFR [47].

Major Adverse Events
After excluding trials with a high risk of bias, the data in 23 trials with moderatehigh quality were available for pairwise meta-analysis. In these trials reporting the major adverse events, including muscle-related adverse outcomes and ALT/AST elevation, no significant difference was observed between PS and HS alone, ES and LS, F and placebo, or LS and placebo/no drug treatment (Supplementary Section S6.5, p. 61).

The Benefits and Harms of Other Hypolipidemic Agents and Polyunsaturated Fatty Acids Supplementation
Based on the findings from the related moderate-high quality RCTs [48][49][50][51], supplementation with ω-3/ω-6 could effectively improve lipid metabolism disorder by reducing the LDL/HDL-c ratio without an obvious effect of decreasing LDL-c in dialysis patients. According to the studies with a low-moderate risk of bias investigating the benefits of colestilan in ESRD individuals [52][53][54], the LDL-c-reducing effect of colestilan was significant and even not inferior to simvastatin. During the treatment phase, except for gastrointestinal reactions and some other mild-moderate drug-related adverse events, no serious side effects were observed in dialysis patients. In addition to traditional agents, the application of one new antidyslipidemic medicine, Apabetalone, was discovered to decrease major cardiovascular events by 50% in CKD and diabetes patients with a high burden of arteriosclerotic cardiovascular disease [55]

Discussion
This systematic review and NMA summarized the latest evidence for the benefits and safety of current antidyslipidaemic pharmacotherapies among moderate-advanced CKD. Compared with the previous pairwise meta-analysis, NMA compared the effects of various medicines and provided more information. In addition to the benefits of statins (with or without ezetimibe) [4,6,7,56,57], this NMA further concluded the value of other hypolipidemic agents, especially PCSK9i. All 18 RCTs involving 41,213 participants provided moderate certainty evidence that compared to placebo or no hypolipidaemic therapy, PS, HS, and LS were associated with a significant reduction in all-cause mortality among CKD patients. For long-term composite cardiovascular events, moderate certainty evidence provided by 20 trials enrolling 42,286 CKD patients supported the benefit of PS, HS, LS, and F on risk reduction. Low certainty evidence supported the significant association between ES and composite cardiovascular events reduction. These pharmacotherapies benefit CKD patients without leading to serious adverse events or a negative influence on renal function. Of note, studies of low-risk indicated that statins might exert a dose-dependent beneficial effect on renal function. Regarding the application of other traditional agents, we concluded that colestilan was an effective and well-tolerated treatment for LDL-c reduction in CKD even in the dialysis group, without evidence supporting longterm cardiovascular risk reduction. Apabetalone was expected to dramatically improve the prognosis of CKD patients.
Statins effectively reduced all-cause death and composite cardiovascular events in CKD, which was consistent with the findings of previous meta-analyses and the recommendations for statin application in CKD [6]. In addition, our work provided some other important information. Firstly, compared to previous works enrolling all CKD patients including those with eGFR of 60-90 mL/min/1.73 m 2 , our study supported the consistent treatment effect in moderate-advanced stage patients. Secondly, in contrast to the opinion in the KDIGO Clinical Practice Guideline that HS in CKD was not recommended given its uncertain safety [6], our study indicated that this prescription might be associated with a greater magnitude of risk reduction, with no or few serious adverse events and a negative influence on renal function. Being characterized as having a high/very high risk of ASCVD, CKD patients may reap additional benefits from aggressive statin therapy. However,

Discussion
This systematic review and NMA summarized the latest evidence for the benefits and safety of current antidyslipidaemic pharmacotherapies among moderate-advanced CKD. Compared with the previous pairwise meta-analysis, NMA compared the effects of various medicines and provided more information. In addition to the benefits of statins (with or without ezetimibe) [4,6,7,56,57], this NMA further concluded the value of other hypolipidemic agents, especially PCSK9i. All 18 RCTs involving 41,213 participants provided moderate certainty evidence that compared to placebo or no hypolipidaemic therapy, PS, HS, and LS were associated with a significant reduction in all-cause mortality among CKD patients. For long-term composite cardiovascular events, moderate certainty evidence provided by 20 trials enrolling 42,286 CKD patients supported the benefit of PS, HS, LS, and F on risk reduction. Low certainty evidence supported the significant association between ES and composite cardiovascular events reduction. These pharmacotherapies benefit CKD patients without leading to serious adverse events or a negative influence on renal function. Of note, studies of low-risk indicated that statins might exert a dose-dependent beneficial effect on renal function. Regarding the application of other traditional agents, we concluded that colestilan was an effective and well-tolerated treatment for LDL-c reduction in CKD even in the dialysis group, without evidence supporting long-term cardiovascular risk reduction. Apabetalone was expected to dramatically improve the prognosis of CKD patients.
Statins effectively reduced all-cause death and composite cardiovascular events in CKD, which was consistent with the findings of previous meta-analyses and the recommendations for statin application in CKD [6]. In addition, our work provided some other important information. Firstly, compared to previous works enrolling all CKD patients including those with eGFR of 60-90 mL/min/1.73 m 2 , our study supported the consistent treatment effect in moderate-advanced stage patients. Secondly, in contrast to the opinion in the KDIGO Clinical Practice Guideline that HS in CKD was not recommended given its uncertain safety [6], our study indicated that this prescription might be associated with a greater magnitude of risk reduction, with no or few serious adverse events and a negative influence on renal function. Being characterized as having a high/very high risk of ASCVD, CKD patients may reap additional benefits from aggressive statin therapy. However, the value of statins in primary prevention requires further serious assessment since those receiving aggressive treatments enrolled in our work mostly had prior ASCVD. Thirdly, the benefits of statins may not be limited to cardiovascular protection, as their dose-dependent renoprotective properties have been reported by an increasing number of investigators [18,19,58,59]. This is encouraging because a downward trend should otherwise have been expected based on the natural history of CKD [60]. The factors accounting for this phenomenon are not well known, in which vascular protection, lipids, CRP reduction, and a decrease in proteinuria may play important roles. However, the absence of Asian participants in those trials influences the generalization to a broader population owing to differences in lipid profiles and medication tolerance. While the effects of statins in protecting cardiovascular health were blunted in dialysis according to the subgroup analysis, indicating that the use of these medications should not be extended to dialysis patients given the uncertain benefit and cumulative drug toxicity. Their cardiovascular events are proportionally increased due to non-atheromatous processes such as sudden death and heart failure [4,7], which would not be directly improved by hypolipidemic treatments [61,62]. However, the limited number of patients enrolled might be underpowered to detect the difference. Moreover, the conventional low-dose statin therapy given the safety among them may not be the optimal choice to maximize benefits. Therefore, the value of lipid-lowering intervention in dialysis patients requires more investigation, especially for patients with additional cardiovascular risks such as existing CAD and higher LDL-c [63].
PS had the highest probability of reducing the occurrence of all-cause death and composite cardiovascular events, suggesting that the addition of PCSK9i was probably associated with further risk reduction. This action may be explained by the dramatic effect on lipid management, especially the potency of reducing LDL-c by approximately 60% on top of statin (±ezetimibe) use. For CKD patients, the cardiovascular risk increases as the eGFR declines, and thus, additional timely intervention is required to enhance cardiovascular protection. However, treatment escalation with a double-dose statin can produce only an incremental LDL-c reduction of 6%, and the clinical benefits are attuned to renal disease progression [64]. Moreover, serum PCSK9, which is inversely correlated with eGFR, was roughly double in CKD patients compared with healthy controls [65]. In this context, PCSK9i is likely to provide additional cardiovascular benefits and has a unique advantage compared to statin monotherapy. However, the extensive use of PCSK9i in practice cannot be achieved currently due to their perceived expense and the limited amount of evidence. Based on the 'highest risk-highest benefit' strategy and related published trials, this powerful antidyslipidaemic agent is considered cost-effective only in patients with clinical atherosclerotic cardiovascular disease and other comorbidities [4,66]. More clinical information assessing the efficacy and safety profile is needed before PCSK9-targeted therapy can be recommended to CKD patients for primary prevention. Furthermore, a critical question is whether PCSK9i can remain effective in preventing adverse cardiovascular events as kidney impairment progresses, even in dialysis. Our analysis further stresses the additional value of PCSK9i in CKD and indicates the need for investigators to assess the cost-effectiveness of wide application in the general CKD population.
The combination of statin and ezetimibe failed to lower death risk effectively, which might be because the CKD patients enrolled in SHARP, the key source of evidence related, were mostly at stage4-5 and even dialysis individuals with a very high risk of death induced by non-atherosclerosis-related diseases. Currently, the analysis of ES in CKD was restricted to a limited number of related RCTs. Although it was proven to be associated with the reduction of composite cardiovascular events, the grade of evidence was low. Therefore, the investigation of ES, especially the comparisons between ES and statin monotherapy in CKD, is needed urgently. And the optimality of this prescription in guidelines should be re-evaluated with the progress of antidyslipidemia pharmacotherapy.
Fibrates with/without statins could effectively further improve lipid parameters (especially TG and HDL-c) and reduce total cardiovascular events [15,33,47,67] among CKD persons. CKD persons are frequently characterized as having high TG but normal LDL-c levels, which might explain their benefit, as their effect on cardiovascular-related outcomes among general persons had been proven to be equivocal and more evident in those with higher TGs/lower HDL-c [4,68]. However, the limited number of studies included in our work made this evidence less robust and the studies on dialysis patients were absent. Therefore, the CV benefits require more confirmation and the ongoing PROMINENT trial may provide additional information [69]. As for the application of the other traditional agents and fish oil, the sparsity of evidence hampered the investigation of the association between them and risk reduction. Apabetalone was expected to dramatically improve the prognosis of CKD patients [55].
Hypolipidemic medications protect cardiovascular health through pleiotropic pharmacological mechanisms, such as lipid reduction effects and the stabilization of atherosclerotic plaques. However, there is conflicting information on the explanations accounting for their cardiovascular protective effects in CKD regarding their unique pathophysiological characteristics. First, the link between serum lipid levels and the cardiovascular outcome is not clear in CKD, with debates surrounding the role of LDL-c, which is often within normal limits [3]. The relation between LDL-c and cardiovascular risk was deemed less robust and the KDIGO guidelines rejected treat-to-target goals [6]. However, there were still several large trials reporting the association between per 1 mmol/L LDL-c and overall risk reduction [23], and the magnitude of risk reduction among these medications remained roughly consistent with that of LDL-c reduction in our work. Except for the discussion on LDL-c, the effect of other components of lipid profiles, especially TG and HDL-c with reversed functions, has also drawn attention in recent years [70]. Second, inflammation is a key process observed in CKD and has been shown to predict the long-term risk of developing atherosclerotic vascular disease events and death. Lipid-lowering agents, particularly statin-based therapy and PCSK9i, could protect cardiovascular health by attenuating the inflammatory response [19,31,32,[71][72][73][74][75] and achieve the largest effect on relative risk reduction among patients who reduced not only LDL-c by more than 50% but also hs-CRP levels by more than 50% [19]. Last, the effects of reducing proteinuria, a potential risk factor for CAD, may contribute to the decrease in cardiovascular events, and this benefit was independent of the influence on lipids [76].
This work had some limitations. (1) Although this study was based on the relevant articles of the highest quality of evidence available currently, the results should be treated seriously since some data obtained from reported post hoc analyses of RCTs might be less reliable. We will update this work accordingly when additional valuable data become available. (2) There was an imbalanced distribution of participants among treatment strategies. As the network plots showed, most included trials studied the effects and safety of low-intensity statins, while the trials focusing on other drug regimens were limited.

Conclusions
In conclusion, this systematic review and Bayesian NMA provide a comprehensive overview of the state of the evidence available concerning the effects and safety of hypolipidemic medications in CKD patients. Despite comorbid ASCVD and LDL-c levels, statin-based treatment could effectively reduce long-term all-cause mortality and composite cardiovascular events in nondialysis CKD populations. Aggressive therapies, such as PS and HS, appeared to be more effective, without causing major adverse events or further impairment of renal function. In addition to their cardioprotective value, statins were reported to have potential dose-dependent renoprotective properties. The present work was an update of the previous meta-analysis, and the first one to summarize and rank the effect of various lipid-lowering drugs in CKD, with the expectation to provide some reference for clinical practical and further research.
Author Contributions: Research idea and study design: Y.P., G.L. and Y.L.; Data sources and searches: G.L., X.W., X.C., K.H., L.B. and Y.Y.; data analysis/interpretation: Y.P. and G.L.; statistical analysis: G.L.; supervision or mentorship: Y.P. and Y.L. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. Y.P. takes responsibility that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.

Data Availability Statement:
The analytic dataset is available on request by contacting the corresponding author.