Demographic information
A total of 1,959 individuals signed informed consent and participated in completing the questionnaire. The demographic information of participants is listed in Table 1. These participants represent 104 rare diseases and those diseases remaining undiagnosed after repeatedly visiting the hospital. The average onset age is 36.8±85.1 months, while the average diagnosis age is 56.5±110.0 months (95% CI 51.6 to 61.4). The diagnosis was delayed for 16.2±35.4 months (95% CI 14.6 to 17.8). Interestingly, 497 patients (26.1%) were diagnosed through newborn screening. When patients diagnosed through newborn screening were excluded, the diagnosis was delayed for 24.3 ± 41.8 months (95% CI 22.1 to 26.5), with the onset age being 48.6 ± 95.0 months (95% CI 43.6 to 53.6), and diagnosis age being 77.9 ± 122.7 months (95% CI 71.5 to 84.3). During the diagnosis odyssey, patients visited 3.2±2.4 hospitals (95% CI 3.1 to 3.3), and experienced 1.6±3.8 misdiagnoses (95% CI 1.4 to 1.8). A total of 1,770 participants provided information about 139 hospitals where the diagnoses were made. The hospitals that diagnosed more than 20 participants of this study were listed in 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 figure 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 financial 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 helpful. A total of 560 patients (30.6%) had never received genetic counseling. Most respondents (72.6%) believed that their doctors did not have sufficient information about rare diseases. Most respondents (82.1%) deemed newborn screening to be extremely important.
Orphan drugs and medical cost
As shown in Fig. 2, most respondents (57.7%) rated the availability of orphan drugs as extremely poor, and 456 individuals (23.7%) rated it as poor. As to the affordability of orphan drugs, most respondents (72.3%) rated it as extremely poor (43.0%) or poor (29.3%). Most respondents (50.4%) had spent 5-50% of their annual family income on the medical cost of rare diseases, 526 respondents (27.7%) had spent 50-100% of income, and 231 (12.2%) had spent >100% of income. These results indicate that rare diseases caused a significant financial burden. As to the specific types of medical insurance, most respondents (59.6%) had Basic Medical Insurance Systems for Urban and Rural Residents, 404 (20.8%) had Medical/Social Insurance Program for Children, and 112 (5.8%) had no medical insurance. However, only 0.8% (16/1,913) of the individuals had orphan drug costs fully covered by insurance, 50.2% individuals had partial coverage, while the medical cost of 48.1% individuals was not covered by insurance at all. Out of 1,936 respondents, 877 (45.3%) recommended to implement special insurance program for rare diseases, 847 (43.8%) recommended to include rare diseases into Critical Illness Insurance Program, a national medical insurance program. Only 8 individuals (0.4%) believed that the current insurance system is sufficient. These results demonstrate that there lacks sufficient support from the medical insurance system.
Difficulty in life, education, and employment
Patients and care-givers are also often disadvantaged in employment, education, and social life 27. In this study, only 37.6% of respondents did not need any assistance, while the remaining 62.4% needed different levels of assistance. However, 83.0% of patients had no disability certificates, which are issued by the government to provide benefits and protection. Out of 1,830 respondents, 725 (39.8%) found no available barrier-free facilities, and 490 (26.9%) found very few such facilities. Only 61 (3.4%) and 277 (15.2%) believed that available barrier-free facilities could completely or largely meet their needs, respectively. Most respondents (59.7%) had experienced difficulty in education. As to the main financial source of patients, 69.6% of respondents relied on the income of their family members, and only 215 (11.4%) relied on their own income. Only 88 (4.7%), 23 (1.2%) and 65 (3.5%) of patients had full-time, part-time jobs, or free-lancers, respectively. A total of 823 patients (43.8%) were children or retired, 549 (29.2%) were in college and continuing education, and 333 (17.7%) were unemployed. Most respondents (62.0%) believed that patients had experienced difficulty in finding jobs. Regarding the specific challenges in finding jobs, 340 out of 1,024 respondents (33.2%) attributed it to ‘insufficient opportunities’, 264 (25.8%) chose ‘discrimination’, 233 (22.8%) chose ‘lack of skillsets’, and 178 (17.4%) chose ‘lack of special employment agencies’.
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). A total of 616 individuals (63.6%) suggested these organizations should ‘obtain more philanthropic support’, 614 (63.4%) suggested they could ‘provide more disease-related information and guidance’, 601 (62.1%) suggested ‘advocacy for legislations’, 579 (59.8%) suggested ‘raise rare disease awareness’, 424 (43.8%) suggested ‘protect patient rights’, and 267 (27.6%) suggested ‘maintain an equal and respectful environment for communication’. The information needs of patients and care-givers were also assessed (Fig. S1C). Out of 1,923 respondents, 1,538 (80.0%) selected information about ‘treatment’, 1,429 (74.3%) selected ‘research progress’, 1,282 (66.7%) selected ‘medical insurance’, and 1,089 (56.6%) selected ‘contact information of experts’. Currently, most respondents (70.1%) obtained relevant information through social media, 1,074 (54.8%) through physicians, 864 (44.1%) through websites, 675 (34.5%) through patient meetings. As to the preference of information source, 1,419 out of 1,911 respondents (74.3%) mentioned social media, 1,334 (69.8%) selected physicians, and 1,207 (63.2%) selected websites. There is clearly a discrepancy between information obtained and information the patient hoped to obtain from physicians. Participants also made recommendations for 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. Firstly, results using the SF-36, patients and care-givers had remarkably lower scores in all domains than healthy populations (Table 2). With the PHQ-9, 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, patients had an average score of 9.0 (95% CI: 8.3 to 9.6), and care-givers 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 their average scores were significantly higher than normative values from the healthy population. With regard to PHQ-15, 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 markedly higher than normative values in healthy populations. Results from the PSQI showed that 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 significant 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.
Furthermore, 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. Specifically, 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 significantly lower score in GH of SF-36 than care-givers (difference= -11.327, adjusted p=0.001), indicating that the disease burden significantly 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.