Multi-criteria decision analysis of value evaluation of rare disease medical insurance drugs in China

Abstract

Background

According to the selection criteria outlined in China’s current basic medical insurance system, the majority of drugs for rare diseases fail to meet the requirements for inclusion. Consequently, patients with rare diseases lack sufficient protection for their fundamental rights to life and health. The purpose of this paper is to explore the construction of a multi-criteria decision analysis (MCDA) system for the inclusion of rare disease drugs in medical insurance.

Methods

A preliminary evaluation system was constructed through a systematic literature review, followed by the establishment of a formal evaluation system through expert investigation. Based on the formal system, expert surveys were conducted to score the system attributes, and the pairwise comparison method was used to calculate the weight contribution value of each attribute in the system. The robustness of the system was tested using the bootstrap method.

Results

A multi-criteria decision value evaluation system for the inclusion of rare disease drugs in medical insurance, comprising four primary attributes and 16 secondary attributes, was developed. The four primary attributes and their respective weight contributions are as follows: disease-related aspects (26.6%), treatment-related aspects (25.8%), economic-related aspects (24.0%), and social-related aspects (23.6%). Bootstrap validation confirmed the stability of the system results (p < 0.05).

Conclusion

This study initially constructed a value evaluation system for the inclusion of rare disease drugs in medical insurance, based on MCDA and multi-stakeholder perspectives. However, the system relied heavily on expert opinions and lacks empirical analysis. Given the complexity of real-world applications, further validation is necessary to assess the system’s applicability and feasibility.

Background

Rare diseases, also known as “orphan diseases”, are conditions with very low prevalence, and are increasingly gaining attention in health policy. More than 6000 rare diseases affect over 300 million people worldwide [1]. The various disabilities caused by rare diseases, as well as the uncertainty in diagnosis and treatment, have been shown to significantly impact the health, psychosocial well-being, and economic status of families affected by these conditions [2]. However, fewer than 10% of rare diseases have an approved treatment drug or regimen.

Orphan drugs are medicinal products used to diagnose, prevent, or treat rare diseases [3]. The development of these drugs faces significant challenges due to small populations of target patients and high costs of production, which often lead to high market prices. In order to improve the accessibility of drugs for patients with rare diseases, many countries are now actively exploring how to conduct scientifically valid and accurate evaluations of orphan drugs’ clinical value, with the goal of incorporating high-value orphan drugs into national health insurance reimbursement schemes [4].

Health Technology Assessment (HTA) is commonly used to evaluate the value of pharmaceutical products. HTA has traditionally relied on cost-effectiveness analysis as a cornerstone for evaluating new therapies, assessing the clinical validity and utility, the efficacy, and the cost-effectiveness of new interventions [5]. The most common criteria for HTA include cost-benefit measures based on indices such as quality-adjusted life years and incremental cost-effectiveness ratios [6, 7]. However, the application of HTA to orphan drugs faces significant challenges [6]. These include inherently small patient cohorts for clinical trials, resulting in limited data availability and uncertain therapeutic effectiveness. Additionally, the high development costs of orphan drugs often conflict with traditional cost-effectiveness thresholds, while ethical concerns regarding societal value and equity further complicate evaluation through HTA frameworks [7–13]. Some healthcare systems have begun advocating for methodological adaptations to better capture the unique value of orphan drugs [14]. Proposed strategies include redefining effectiveness criteria beyond traditional metrics, prioritizing patient-reported outcomes (PROs), and integrating qualitative assessments of therapeutic impact [15]. These adjustments aim to address the multidimensional value of orphan drugs, encompassing clinical, social, and ethical dimensions, thereby fostering more equitable and inclusive access to these critical therapies.

Multiple criteria or multi-criteria decision analysis (MCDA) collectively refers to formal approaches that support decision-making by taking into account multiple criteria explicitly and transparently. MCDA provides a comprehensive framework for evaluating the value of a drug for a rare disease from multiple perspectives [16]. It involves applying multiple attitudes to assess the value of medicines from the perspective of various stakeholders in a comprehensive manner [9]. MCDA method is currently an internationally accepted approach for evaluating the value of medicines [17]. Many countries have implemented specific guidelines for evaluating the value of medicines for rare diseases, intending to include them in health insurance coverage. These guidelines take into account ethical and social fairness factors, and may also relax the requirements for pharmacoeconomics assessments [18]. Additionally, they consider various external factors at multiple levels [16]. The application of MCDA in the comprehensive evaluation of orphan drugs has been explored and implemented in several countries. For example, a study in Spain conducted an MCDA analysis of Selexipag, a treatment for pulmonary arterial hypertension, demonstrating the application of this method in assessing the value of orphan drugs [17]. The selection of criteria varies across countries, depending on the national situation, system, economic level, population characteristics, and level of research. However, there are also certain generalities and commonalities.

In China, the government has always attached great importance to the situation of rare disease patients, and increasingly focused on exploring pharmaceutical policies for rare diseases. There are over 20 million rare disease patients in China, and the government has conducted registration studies on 171 rare diseases, with 68,408 rare disease patients being registered [19]. Two batches of rare diseases catalogs were released around 2018 and 2023, collectively covering 207 rare diseases. In 2019, through price negotiations, several rare disease drugs were included in the national medical insurance drug list for reimbursement for the first time [20], with additional drugs for rare diseases subsequently included [21, 22]. Currently, China mainly relies on a multi-level medical security system including the national and local medical insurance, serious illness insurance, and special assistance to support patients with rare disease, improve the availability of drugs, and alleviate their burden. However, the current multi-level medical insurance system for rare disease drugs still faces numerous challenges, such as the lack of comprehensive top-level design, unclear and non-transparent drug value standards, which need to be further improved.

In this study, we conducted a comprehensive evaluation of the value of rare disease drugs from a multi-stakeholder perspective, focusing on how to select high-value rare disease drugs for inclusion in national health insurance, and what factors should be considered in the selection process. Our objective was to explore and construct a multi-criteria attributes system for evaluating the inclusion of rare disease drugs in China’s health insurance system from the perspective of multi-stakeholder strategies, guided by MCDA method.

Methods

The study was conducted in four phases (Fig. 1). In the first phase, we identified and defined the initial criteria attributes to be considered when including rare disease drugs in medical insurance coverage through a literature review. In the second phase, we conducted a preliminary survey of the initial attributes system and added one additional attribute to finalize the criteria. In the third phase, we carried out the final survey of the attributes system and analyzed the survey results using the pairwise comparison method to calculate the weight coefficients. In the fourth phase, we presented the findings to the expert group for discussion and feedback. The bootstrap analysis method was used to test the stability of the results.

Fig. 1.

Progress of the study

Phase ONE: selection and definition of the attributes

The initiation of this research endeavor primarily involved the selection and definition of the attributes to be considered for inclusion of orphan medicinal products (OMPs) in reimbursement decisions. This was achieved through a comprehensive review of the literature and an analysis of relevant regulatory frameworks.

First, a literature review was conducted by searching relevant articles in major databases such as PubMed, CNKI, Web of Science, and other related search engines. The focus was on the publications utilizing the MCDA methodology, while also synthesizing the literature on factors influencing the valuation of drugs for rare diseases. After a meticulous review of the literature, irrelevant articles were excluded. All attributes relevant to the value evaluation of the OMPs were extracted, and the numerous attributes were then categorized, merged, and summarized to obtain the final index.

In addition, relevant policy documents were also reviewed to ensure the understanding and incorporation of national policy perspectives. This dual-strategy approach aimed to capture both scholarly insights and real-world policy considerations. Ultimately, the attributes for evaluating the value of OMPs were defined, and a preliminary framework for the value assessment system was established. These attributes must be mutually independent and non-overlapping. Subsequently, an online expert survey questionnaire was designed based on the preliminary attribute system to gather opinions and suggestions from multidisciplinary experts, informing the subsequent revision of the initial system.

Phase TWO: pilot survey and the attributes revision

An online survey questionnaire was designed. The questionnaire encompassed a survey of the experts’ basic information, as well as the initial proposals and opinions on the preliminary attributes along with their levels. A pilot survey was conducted with a small group of participants to gather relevant data and insights from experts, as well as to evaluate the effectiveness and appropriateness of the initial attributes system. The preliminary findings from this survey served as the foundational for the subsequent research endeavors.

The results of the pilot survey were presented to the expert panel via an online meeting, with the goal of reaching consensus among experts on the selection, definition, and design of the attributes and their levels. The expert panel could modify attribute definitions or recommend excluding specific attributes. Based on the survey results and expert discussions, a consensus was achieved, yielding a final questionnaire and a final attributes system.

Phase THREE: expert panel identification and weighting attributes

A second survey was conducted using the final questionnaire to gather additional insights. At this stage, a final panel of experts was identified and invited to assign their final scores to the attributes. The selection of experts was based on their professional profiles and experience in relevant fields. The resulting multidisciplinary panel comprised 30 distinguished experts, including leaders and representatives from rare disease organizations (n = 6), health economics specialists (n = 4), physicians (n = 5), health authority officials (n = 6), business representatives (n = 2), pharmacists(n = 5), and public representatives (n = 2). Among them, 11 hold doctoral degrees or above, 22 have intermediate or higher professional titles, 20 have over 10 years of work experience, and 90% are familiar with issues related to rare diseases and drug policies.

The study was conducted through a combination of online and offline modes. The first step involved several online and offline sessions where participants received fundamental training on the MCDA methodology. The second step required participants to rate the value framework criteria independently, indicating the relative significance of each criterion, regardless of the interventions assessed. Participants assigned relative weights to each criterion using a simple hierarchical five-point scale (one = lowest relative importance, five = highest relative importance). The third step involved presenting the scores to a panel of experts and collecting their opinions.

The pairwise comparison method has emerged as a highly viable approach for low- and middle-income countries [12]. We assigned weights to various attributes, calculating the average scores of each attribute by constructing a judgment (pairwise comparison) matrix. This matrix facilitated the computation of weight coefficients for the attribute at each hierarchical level.

Phase FOUR: deliberative process

In the final stage, the results derived from the pairwise comparison method, calculated based on weighted attributes, were presented to the expert panel for deliberative recommendations. Given the limited expert sample size, robustness was verified through the bootstrap method with 1,000 replications. All the data in this study were analyzed using SPSS, including computation of the authority coefficient, coefficient of variation, and Kendall coefficient of concordance (W) and W test. A p value less than 0.05 was considered significant.

Results

The attributes definition and determination of criteria system

Through the comprehensive systematic literature review [2–4, 9, 17, 23–44], we screened and consolidated initial attributes, eliminated redundancies after careful discussion, and thus identified 15 preliminary attributes. Subsequently, based on the results of the pilot survey and expert discussions, an additional attribute, costs avoided by treatment, was incorporated into the initial system. Ultimately, the definitions of each preliminary attribute were determined, and a final attribute system was established, consisting of four primary attributes (disease-related aspects, treatment-related aspects, economic-related aspects, and social-related aspects), and supported by 16 secondary attributes, including disease rarity, age of target population, severity of rare diseases, unmet needs, drug safety, drug efficacy, quality of evidence, PROs, drug cost-effectiveness, annual treatment cost, budget-impact analysis, costs avoided by treatment, reimbursement status in other countries or agencies, government objectives and priorities, moral and ethical considerations, and drug innovation (Table 1).

Table 1.

Reimbursement attributes for orphan drugs

Name of the attributes	Definition
Disease-related aspects
1. Disease rarity	Prevalence and patient population size
2. Age of target population	Age at the beginning of treatment of the disease
3. Severity of rare diseases	The impact of disease on patients’ survival period; Mortality rate and disability rate of the disease; The impact of disease on patients’ quality of life; The impact of disease on caregivers’ quality of life
4. Unmet needs	Unmet need for effectiveness; Unmet need for security; Unmet need for patients to report outcomes; Patient’s needs
Treatment related aspects
1. Drug safety	Security (both short-term and long-term); Adverse reactions (including serious adverse reactions); Tolerance
2. Drug efficacy	Expected clinical benefit or actual clinical benefit; Proportion of the target population attaining the intended health benefit; Onset and duration of health benefit; Other criteria for evaluating effectiveness in specific treatment areas
3. Quality of evidence	Evidence validity (study design, consistency between studies); Relevance of evidence to decision makers (population, disease stage, outcome); Reporting integrity (including uncertainty analysis heterogeneity among findings, limitations on the number of studies, etc.); Type of evidence
4. PROs	Improvements in patients’ health-related quality of life; Impact on autonomous mobility; Impact on personal dignity; Medication convenience, and operational and administrative difficulty
Economic-related aspects
1. Drug cost-effectiveness	Evaluated based on payers’ willingness-to-pay. This evaluation utilizes the incremental cost-effectiveness ratio, expressed as the cost per quality-adjusted life year gained when compared to a comparator or standard treatment.
2. Annual treatment cost	Average cost per patient per year
3. Budget impact analysis	The national budget impact of the inclusion of drugs in medical insurance reimbursement or the affordability of healthcare funds
4. Costs avoided by treatment	Medical costs: net drug costs, procurement costs, and implementation/maintenance costs; Other health costs: impact on primary care expenditures, hospitalization expenditures, and long-term health expenditures; Non-medical costs: productivity losses; economic impacts on patients and caregivers; broader societal costs
Social-related aspects
1. Reimbursement status in other countries or agencies	The existence of drug reimbursement policies in other countries or institutions
2. Government objectives and priorities	Rare disease program; Status of drugs for rare diseases; Other relevant priorities
3. Moral and ethical considerations	Ethics or fairness considerations for vulnerable groups
4. Drug innovation	Innovation defined by not being listed in any domestic or international regulatory market.

The evaluation of the criteria system

The degree of concordance among expert opinions is shown in Table 2. The W values for the primary and secondary attributes in the first survey were 0.086 and 0.108, respectively, and 0.237 and 0.156 in the second survey. According to the chi-square test, the W value of the primary attributes in the first survey was not statistically significant (p > 0.05), while the W of the secondary attributes was statistically significant (p < 0.05). In the second survey, the W value for both the primary and secondary attributes were statistically significant (p < 0.001). Compared with the first survey, the second survey targeting the final attributes system demonstrated a higher degree of concordance among the expert opinions.

Table 2.

Level of multi-stakeholder opinion alignment

	Attributes	Coefficient of variation	W	χ2	p-value
The first survey	Primary	0.039	0.086	6.445	> 0.05
	Secondary	0.059	0.108	37.856	< 0.05
The second survey	Primary	0.048	0.237	21.372	< 0.001
	Secondary	0.047	0.156	70.003	< 0.001

The evaluation of the attributes

Based on the pairwise comparison method and the comprehensive perspective of multiple stakeholders, we calculated the average weight coefficients of each attribute in the final criteria system from both the overall perspective and the stratified perspective of experts from different fields, as shown in Table 3. Considering the holistic framework of reimbursement criteria, the relative importance of each criterion compared to others was determined.

Table 3.

Attribute evaluation results

Attribute weightings	All participants (n = 30)	Representatives of rare disease organizations (n = 6)	Health economics experts (n = 4)	Physicians (n = 5)	Health authorities (n = 6)	Business representatives (n = 2)	Pharmacists (n = 5)	Public representatives (n = 2)
Disease-related aspects	0.266	0.266	0.279	0.279	0.250	0.250	0.230	0.294
1. Disease rarity	0.0700	0.0665	0.0766	0.0783	0.0644	0.0645	0.0656	0.0779
2. Age of target population	0.0633	0.0641	0.0676	0.0681	0.0619	0.0565	0.0562	0.0692
3. Severity of rare diseases	0.0705	0.0689	0.0676	0.0749	0.0644	0.0726	0.0718	0.0779
4. Unmet needs	0.0622	0.0665	0.0676	0.0579	0.0593	0.0565	0.0593	0.0692
Treatment-related aspects	0.258	0.257	0.250	0.267	0.260	0.250	0.265	0.235
1. Drug safety	0.0640	0.0654	0.0635	0.0676	0.0630	0.0571	0.0648	0.0588
2. Drug efficacy	0.0660	0.0654	0.0635	0.0707	0.0657	0.0643	0.0677	0.0588
3. Quality of evidence	0.0635	0.0607	0.0595	0.0646	0.0657	0.0643	0.0677	0.0588
4. PROs	0.0645	0.0654	0.0635	0.0646	0.0657	0.0643	0.0648	0.0588
Economic-related aspects	0.240	0.239	0.235	0.244	0.230	0.250	0.253	0.235
1. Drug cost-effectiveness	0.0602	0.0619	0.0543	0.0618	0.0598	0.0645	0.0610	0.0588
2. Annual treatment cost	0.0622	0.0642	0.0579	0.0618	0.0575	0.0645	0.0701	0.0588
3. Budget impact analysis	0.0583	0.0573	0.0615	0.0587	0.0552	0.0565	0.0610	0.0588
4. Costs avoid by treatment	0.0593	0.0550	0.0615	0.0618	0.0575	0.0645	0.0610	0.0588
Social-related aspects	0.236	0.239	0.235	0.209	0.260	0.250	0.229	0.235
1. Reimbursement status in other countries or agencies	0.0562	0.0591	0.0510	0.0516	0.0598	0.0703	0.0512	0.0549
2. Government objectives and priorities	0.0611	0.0613	0.0627	0.0544	0.0650	0.0625	0.0602	0.0627
3. Moral and ethical considerations	0.0618	0.0613	0.0667	0.0516	0.0650	0.0625	0.0633	0.0627
4. Drug Innovation	0.0569	0.0568	0.0549	0.0516	0.0650	0.0547	0.0542	0.0549

The results of the average weight coefficients of the attributes for value assessment of rare disease drugs for inclusion in China’s medical insurance showed that the primary attributes, ranked from high to low, were disease-related aspects (26.6%), drug treatment-related aspects (25.8%), economic-related aspects (24.0%), and social-related aspects (23.6%). The five most-weighted secondary attributes were severity of rare diseases (7.05%), disease rarity (7.00%), drug efficacy (6.60%), drug safety (6.40%) and annual treatment cost (6.22%). Experts from various fields assigned varying weights to specific attributes (Table 3). Additionally, to ensure the stability of the results, the bootstrap method was applied. After expanding the sample to 1,000, the results indicated a minimal difference compared to the original values.

Discussion

The strength of this study was its multi-stakeholder perspective. Following existing expert consensus [44], this study included nine categories of stakeholders: patient representatives, physicians, health policy experts, pharmaceutical company representatives, business representatives, specialists in drug development and others, ensuring diversity and comprehensiveness in perspectives. For example, considering the important role of pharmaceutical companies in the inclusion of drugs in health insurance, representatives from these companies were included. Considering the recent preferential policies for innovative drugs in China, the study included specialists in drug development. Notably, the participation of rare disease organization representatives provided insights into patient communities’ genuine needs and priorities [31].

According to the study results, the primary attributes with higher weights were treatment-related aspects and disease-related aspects. This indicated that when evaluating rare disease drugs for medical insurance inclusion, stakeholders prioritized the disease itself and its impact on patients, followed by the safety and effectiveness of the orphan drugs. For the secondary attributes, stakeholders prioritized (1) disease severity in disease assessment aspect; (2) drug efficacy in drug treatment aspect; and (3) annual treatment cost in economic evaluation aspect. They also emphasized ethics or fairness considerations for vulnerable groups.

The results of this study revealed field-specific differences in how stakeholders weighted each attribute.

Disease-related aspects

Public representatives gave the highest scores to disease-related attributes, indicating their greater awareness and empathy for patients’ conditions. In contrast, pharmaceutical experts assigned the lowest scores, likely reflecting their professional focus on drug development rather than the broader context of the disease.

Treatment-related aspects

The public assigned lower scores to treatment-related attributes, while drug experts and doctors assigned higher scores. This divergence might arise from the public’s limited understanding of the technical details of drug treatment, leading them to prioritize patient health over the intricacies of drug therapy.

Economic-related aspects

Most stakeholders assigned lower scores to economic-related attributes, which may reflect widespread concerns about the economic feasibility of rare disease drugs. However, business representatives and drug experts gave higher scores, possibly due to their deeper understanding of the high costs associated with drug research and development, leading to a more pragmatic perspective. Notably, both economists and policymakers assigned relatively low scores to economic factors, a trend that likely stems from the recognition of the inherent limitations of traditional cost-benefit analysis methods in the context of rare disease drug reimbursement [45, 46].

Socially-related aspects

Policymakers placed the highest emphasis on socially relevant factors, consistent with their regulatory responsibilities. On the contrary, doctors, who primarily focus on disease and drug treatment, assigned significantly lower weights, reflecting their prioritization of medical aspects over social considerations.

Given the symbiotic relationship between policymakers and multiple stakeholder advocacy groups, collaborative efforts are imperative for the development of practical policies. While governmental bodies have the authority to establish and enforce policies related to rare diseases, it is the rare disease groups that ultimately act as the primary driving force. These groups not only contribute valuable insights and perspectives but also wield considerable influence over the effectiveness of the policy. Consequently, policymakers must actively engage with related organizations and integrate their expertise to ensure that policies align with the practical needs and concerns of those directly affected by rare diseases. Acknowledging the unique expertise and impact of these groups is crucial for crafting policies that are not only well-informed but also resonate with the diverse challenges faced by the rare disease community.

In addition, our findings were largely consistent with existing research which found that clinical treatment-related factors, disease-related factors, and drug safety were generally given higher weights, while drug innovation and economic-related aspects were given relatively lower weights. While several European studies have highlighted unmet needs as a critical factor, particularly given the limited availability of therapies for rare diseases [36], research on China indicates that unmet needs and patient preferences have received insufficient attention [47]. Therefore, we placed special attention on these aspects in our study, including relevant patient-reported attributes and patient representatives.

To test the stability of the results, this study employed the bootstrap method for verification and the results showed minimal differences compared to the original values. Further analysis revealed that the scores for the attribute “reimbursement in other countries” exhibited relatively higher variability. This was primarily due to the significantly higher scores assigned to this attribute by business representatives compared to other stakeholders. During follow-up discussions, business representatives pointed out that the development costs of rare disease drugs are exceptionally high, particularly due to expenses incurred during research, clinical trials, and regulatory processes, especially given the limited number of rare disease patients, which highlights the importance of government financial support for enterprises. Despite China’s efforts in encouraging rare disease drug research and protecting patients’ rights, government financial support remains insufficient compared to some developed countries. Specific gaps include the lack of financial incentives, such as subsidies for clinical and non-clinical research, tax credits, application fee waivers, corporate tax exemptions, and market exclusivity [48] . Crucially, the existing financial support in China is primarily confined to government research grants. This disparity underscores a significant gap in the financial ecosystem for orphan drug development in China, amplifying the challenges faced by businesses engaged in rare disease research and development.

Overall, our research comprehensively engaged multiple stakeholders, provided a broader perspective, and pioneered a value evaluation system framework for the inclusion of orphan drugs in China’s medical insurance. This study offers an important insight that strengthening cooperation and communication among multiple stakeholders may be essential for developing practical, effective, and feasible policies adapted to China’s specific context.

Limitations

First, this study heavily relied on expert opinions and judgments, which may introduce subjective bias due to varying professional perspectives and expertise levels. Although the participation of diverse stakeholders has partially mitigated this bias, further optimization of data collection methods and expert communication mechanisms to enhance the transparency and credibility of the assessment process remains necessary [49]. Second, the framework remained largely theoretical, and its performance has not been tested in real-world decision-making. Future studies should further test its applicability and effectiveness through pilot programs or retrospective analyses [16, 50]. Lastly, the international applicability of the findings may be limited. Despite some commonalities across countries, international applicability of these findings may be constrained by variations in reimbursement mechanisms and policy environments in various nations.

Conclusion

This study, for the first time, established a value evaluation system for the inclusion of rare disease drugs in medical insurance that aligns with China’s specific context, based on a multi-stakeholder perspective and the MCDA method. The evaluation system comprises four primary attributes and 16 secondary attributes. Although the study has certain limitations, it provides an important research foundation for value assessment of rare disease drug’s inclusion in medical insurance and future academic exploration in this field. Further validation of its applicability and effectiveness in real-world settings remains necessary. 

Abbreviations

HTA

Health Technology Assessment

PROs

Patient-reported outcomes

MCDA

Multi-criteria decision analysis

OMPs

Orphan Medicinal Products

Authors’ contributions

RG conceived and designed the study. KC contacted the experts and collected the data. KC and ZC provided substantive edits to the manuscript. RG reviewed and revised the manuscript. YW analyzed the data. KC and JW designed the questionnaire. BJ and YD conducted professional language polishing and contextual adaptation. All authors read and approved the final manuscript.

Funding

This work was supported by the Undergraduate Innovation Research Program of Nankai University (No.202210055920；No.202310055924).

Data availability

The datasets generated by the survey research during and/or analyzed during the current study are included in this document. The questionnaire and the survey database are available upon request.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All the experts surveyed in this study agreed to publish.

Competing interests

The authors declare no competing interests.