A questionnaire-based study to comprehensively assess the status quo of rare disease patients in China

Background: There are over 16.8 million rare disease patients in China, representing a large community that should not be neglected. To provide a basis for policy-makers, a comprehensive analysis of the status quo, unmet needs, diculty caused by the rare disease is essential. Methods: Therefore, a questionnaire-based study of patients and care-givers was performed. Findings: A total of 1,959 patients and care-givers participated, representing 104 rare diseases, such as lysosomal diseases, hemophilia, and muscular dystrophy. The diagnosis was delayed for 1.4 ± 3.0 years, and patients experienced 1.6 ± 3.8 misdiagnoses between 3.2 ± 2.4 hospitals. The hospitals where diagnoses made were highly concentrated in 10 large hospitals (43.8%) and 5 big cities (42.1%), indicating a signicant inequality of medical resources. The disease often led to diculty in social life, education, and employment, as well as nancial burden that was seldom covered by medical insurance. A battery of standardized tests, including SF-36, PHQ-9, PHQ-15, GAD-7, and PSQI, demonstrated poor health status, depression, somatization, anxiety, and sleeping issues among both patients and care-givers (p<0.05). To examine the inuence of age, disease type, and relationship to patients on the scores in these tests, statistical analysis with a general linear model was conducted. It was also shown that poor health, anxiety, depression, somatization, and sleeping problems were more prevalent in patients than in caregivers, and more prevalent in more severe diseases (e.g., hemophilia, Dravet) or undiagnosed than in other diseases. Interpretations: This study identied the lack of rare disease awareness and legislative support as the major challenge to rare diseases in China, and makes key recommendations for policy-makers, including legislating orphan drug act, raising rare disease awareness, and protecting rights in education and employment.


Introduction
A rare disease is any disease that affects a relatively small number of people. There is no universal de nition of rare diseases, and de nitions vary in different countries. There are between 5,000-8,000 rare diseases [1], affecting a total of 400 million patients worldwide [2]. Together, rare diseases affect approximately 6-10% of the population and 3-4% of births [3], thus rare diseases pose a signi cant challenge to the healthcare system. Approximately 80% of rare diseases are genetic, many of which are life-threatening [4]. Most rare disease patients are children, and 30% of patients die before age 5 [5].
Delayed diagnosis and misdiagnosis are common, resulting in inappropriate treatment and poor outcomes [6]. Approximately 95% of rare diseases have no treatment options [5]. Even if treatments exist, the availability and affordability of treatment are often poor, especially in developing countries.
Awareness and knowledge of rare diseases are often lacking, rendering many patients struggling to nd adequate information. Consequently, the emotional, psychological, and nancial impact of a rare disease on patients and care-givers is also considerable.
There is still no o cial de nition of rare diseases in China; therefore, the total number of rare disease patients in China is unknown. It was previously estimated to be 16.8 million [7]. However, this may be a signi cant underestimate considering the population of 1.4 billion. Further, there lacks legislation or medical insurance coverage of rare diseases, resulting in low interest in orphan drug development of the pharmaceutical industry. The rare disease eld is largely underdeveloped due to the lack of rare disease awareness, legislation, pharmaceutical development, and insurance coverage in China. It is essential to have a comprehensive understanding of this eld to provide a basis for legislation. Therefore, this study aims to assess the status quo, unmet needs, recommendations of patients and care-givers. A questionnaire composed of 116 questions including standardized tests (SF-36, PHQ-9, PHQ-15, GAD-7, and PSQI) was sent to patients and care-givers. Key recommendations to support patients, motivate orphan drug development, and improve rare disease awareness, are made based on the results obtains. This is the rst large-scale study to assess patients and care-givers of rare diseases in China.

Ethics statement
The study was approved by the Institutional Ethics Committee of Guangzhou Medical University.
Potential participants were invited, and only those who signed the informed consent participated in this study between March and May 2020. A questionnaire for patients and care-givers, composed of 116 questions, were designed in Chinese. Participants were invited through advertisements on social media and websites. All the participants acknowledged; 1) that they will participate in this study anonymously; 2) that they can decline to answer any of the questions; 3) that they can quit the study at any time; 4) that the results will be published in a scienti c journal without seeking their approval of the manuscript; and 5) that they will not be paid for participating in this study.

Assessment Instruments
The Short Form (36) Health Survey is a 36-item, self-reported survey of health [8]. SF-36 includes 8 domains: physical function (PF), role limitations due to physical problems (RP), bodily pain (BP), general health (GH), vitality (VT), social function (SF), role limitations due to emotional problems (RE), mental health (MH). The score of each domain ranges from 0 to 100, and a low score indicates poor health. The Pittsburgh Sleep Quality Index (PSQI) is a screening tool for sleeping di culty. PSQI consists of 19 items that can be categorized into 7 domains, including subjective sleep quality (SQ), sleep latency (SL), sleep duration (SD), habitual sleep e ciency (SE), sleep disturbance (Dis), sleep medication use (SM), and daytime dysfunction (DD) [9]. The total score of PSQI ranges from 0 to 21, and a high score indicates poor sleep quality. Patient Health Questionnaire-9 (PHQ-9) is a 9-item screening tool for depression [10].
PHQ-9 measures the frequency of depression symptoms over the last 2 weeks. The total score of PHQ-9 ranges from 0 to 27, and scores of ≥ 5, ≥10, and ≥ 15, represent mild, moderate, and severe depression. PHQ-15 is a screening tool for somatization [11]. PHQ-15 measures the severity of individual somatic symptoms during the past 4 weeks. The total score of PHQ-15 ranges from 0 to 30, and scores of ≥ 5, ≥10, ≥ 15 represent mild, moderate, and severe somatization, respectively. Generalized Anxiety Disorder Scale (GAD-7) is a screening tool for anxiety [12]. Each item describes one of the typical anxiety symptoms and measures the frequency of each symptom over the past 2 weeks. The reliability and validity of the Chinese version of SF-36, PSQI, PHQ-9, PHQ-15, and GAD-7 have been con rmed [13][14][15][16][17].
Data analysis SPSS 20.0 was used to analyze data, and a p value < 0.05 (two-tailed tests) denotes statistical signi cance. The scores of SF-36, PHQ-9, PHQ-15, GAD-7, and PSQI largely met normal distribution, therefore, a general linear model was applied. For SF-36, PHQ-9, PHQ-15, GAD-7, and PSQI, only those who completed all questions of each test were included in the quantitative analysis. Mean ± standard deviations and 95% con dence interval (CI) were used to describe continuous outcomes.

Demographic information
A total of 1,959 individuals signed informed consent and participated in the questionnaire. The demographic information of participants is listed in Table 1 Fig. 1A. The top 10 hospitals on the list diagnosed 777 patients (43.8% of total), and they were all located in big cities (Fig. 1B). The top 5 cities diagnosed a combined total of 745 patients (42.1%). There is a clear inequality of medical resources in China. As shown in Fig. 1C, most respondents (79.0%) believed that diagnosis helped to gure out treatment and management options, while 1,530 (78.6%) believed that diagnosis helped to understand the disease cause and progression. Interestingly, 290 individuals (14.9%) thought that diagnosis had negative impacts (depression, anxiety, guilt, denial, discrimination, and nancial stress). As shown in Fig. 1D, 687 of 1,831 respondents (37.5%) had received genetic counseling and believed it to be helpful, 146 (8.0%) believed it to be not helpful, while 227 (12.4%) believed it to be moderately very helpful. A total of 560 patients (30.6%) had never received genetic counseling. Most respondents (72.6%) believed that their doctors did not have su cient information about rare diseases. Most respondents (82.1%) deemed newborn screening to be extremely important.

Needs And Activities
Most respondents (75.4%) had joined patient organizations. As shown in Fig. S1A, among these individuals, 1,351 (94.1%) listed 'communicate disease information' as a major reason to join such organizations, and 1,000 (69.6%) mentioned 'obtain support and guidance from organizations'. Out of 1,889 respondents, 693 (36.7%) rated the performance of patient organizations as 'very good, but can be improved', and 687 (36.4%) rated them as 'extremely good', indicating a general approval of the work of patient organizations. The 968 individuals who did not rate patient organizations as 'extremely good' were questioned on how to improve the work of patient organizations (Fig. S1B) There is clearly a discrepancy between information obtained and information the patient hoped to obtain from physicians. Participants also made recommendations to policy-makers on how to help rare disease patients (Fig. S1D). Out of 1,924 respondents, 1,725 (89.7%) recommended 'support orphan drug development', and 1,681 (87.4%) recommended 'appropriate medical insurance for rare disease patients'.

Quality Of Life
A battery of standardized surveys was employed to assess the quality of life, health status, and psychological status of patients and care-givers. First, as to SF-36, a health assessment tool, patients and care-givers had remarkably lower scores in all domains than healthy populations ( Table 2). As to PHQ-9, a depression screening tool, patients had an average score of 12.1 (95% CI: 11.4 to 12.8), while care-givers had an average score of 9.5 (95%CI: 9.1 to 9.9) ( Table 3). The scores of patients and care-givers were higher than normative values and were in the category of moderate and mild depression, respectively. As to GAD-7, an anxiety screening tool, patients had an average score of 9.0 (95% CI: 8.3 to 9.6), and caregivers had an average score of 7.7 (95% CI: 7.4 to 8.0) ( Table 3). Both patients and care-givers were in the category of mild anxiety, and were signi cantly higher than normative values from the healthy population. As to PHQ-15, a somatization screening tool, the average score of patients was 10.3 (95% CI: 9.6 to 11.0), higher than the cut-off value of medium somatic symptom severity. The average score of care-givers was 8.1 (95% CI: 7.6 to 8.5). The scores of patients and care-givers were signi cantly higher than normative values in healthy populations. As to PSQI, a sleeping di culty screening tool, the average score of patients and care-givers were 8.5 (95% CI: 8.0, 8.9) and 6.9 (95% CI: 6.7, 7.2), respectively. These scores were also higher than normative values, indicating severe sleeping problems. There was a signi cant correlation between all seven domains of PSQI (Table S1), and Cronbach's alpha was 0.798, indicating a good internal consistency. Together, these results demonstrate that the disease burden led to poor health, anxiety, depression, somatization, and sleeping problems in patients and care-givers.  Further, correlations between PHQ-9, PHQ-15, GAD-7, PSQI, and subscales of SF-36 were analyzed (Table  S2). Moreover, the impact of age, disease types, and gender on scores in these tests were analyzed by a general linear model. Relationship (patients or care-givers) only had an impact on the scores of PHQ-15, PSQI, and GH of SF-36. Speci cally, patients had a higher score in PHQ-15 than care-givers (difference = 2.541, adjusted p = 0.004), indicating more severe somatic symptoms. Patients had a higher score in PSQI than care-givers (difference = 1.829, adjusted p = 0.002), indicating more severe sleeping problems in patients. Patients had a signi cantly lower score in GH of SF-36 than care-givers (difference= -11.327, adjusted p = 0.001), indicating that the disease burden signi cantly affected the general health of patients. Disease had an impact on the scores of PHQ-9, PHQ-15, GAD-7, PSQI, and subscales of SF-36 (Table S3). Generally speaking, poor health, anxiety, depression, somatization, and sleeping problems were more severe in patients and care-givers of more severe diseases (e.g., DMD, hemophilia, Dravet) or undiagnosed.

Discussion
Delayed diagnosis and misdiagnosis is common and can lead to delayed and improper treatment, as well as the irreversible progression of the disease [20]. As a result, unnecessary tests and treatments are often conducted, resulting in signi cant cost to patients and the healthcare system [19]. A previous study in 2013 reported that it took 5-7 years and 2-3 misdiagnoses in the USA and UK [21]. Interestingly, the duration between onset and diagnosis in China was 1.4 years, and there were only 1.8 misdiagnoses. This may be because of the increased application of newborn screening over the years in China [22]. It may be also because social media has increased avenues for relevant information and communication between patients. One major reason for the di culty in diagnosis is the limited rare disease awareness among patients, families, and physicians. Similar to a previous study in Europe [23], as believed by patients and care-givers in this study, physicians did not have su cient awareness and knowledge about rare diseases. A recent study among physicians in China also showed a lack of rare disease awareness [24]. Therefore, there is a critical need to include rare disease content in medical education and training. Further, a Chinese information hub of rare diseases was suggested to provide reliable, up-to-date, and 'peer-reviewed' information and guidance. As shown in this study, the majority of patients and care-givers were most interested in information about treatment. Orphan drug development is always expensive and time-consuming, ultimately affecting patients' access to new treatments. Witnessing the success of orphan drug acts in other countries [25,26], there was high support for an orphan drug act in China. Another relevant factor is the low medical insurance coverage, signi cantly affecting the viability of orphan drugs in the Chinese market. This not only affects the orphan drug development in China, but also affects the import of orphan drugs from abroad. Based on the aforementioned results and discussion, key recommendations that outline top priorities that the policymakers in China should consider are listed as follows: 1. Pass an Orphan Drug Act to stimulate orphan drug development; 2. O cial de nition or suggested threshold of rare diseases; 3. Improve rare disease awareness among medical professionals and the general public; 4. Improve the medical insurance coverage of rare diseases; 5. Improve the availability and affordability of prenatal screening, newborn screening, and genetic counseling; 6. Prevent discrimination against rare disease patients in education and employment; 7. Accelerate in importing orphan drugs.

Conclusions
This is the rst large-scale study that quantitatively investigates the current status of rare disease patients in China. This study identi es poor health status, depression, somatization, anxiety, and sleeping issues among both patients and care-givers through standardized test, highlighting the need of psychological and medical support. Also, this study also observes di culties in social life, education, and employment, as well as nancial burden. More importantly, the most urgent and critical need of these patients are treatment/orphan drugs. Therefore, a list of action items is recommended to the policymakers, which include legislating an orphan drug act, raising rare disease awareness, and preventing discrimination.

List Of Abbreviations
National Organization for Rare Disorders (NORD), European Organization for Rare Diseases (EURORDIS), Canadian Organization for Rare Diseases (CORD)

Declarations
Ethics approval and consent to participate The study was approved by the Institutional Ethics Committee of the Guangzhou Medical University, China. All interviewees signed the informed consent and agreed to participated this study voluntarily.

Consent for publication
Not applicable Availability of data and materials The raw data are not publicly available due to the agreement between the investigators and the participants.