The objective of this study was to describe the journey of Chinese patients with AL amyloidosis from symptom onset through to diagnosis. A systematic search was conducted using the predefined search terms amyloid and amyloidosis in both Chinese and English from online medical consultation platforms in mainland China (haodf.com, wy.guahao.com, chunyuyisheng.com, ask.39.net and 91160.com) between January 2008 and April 2021.

All data used and presented in this study were obtained from publicly accessible sources without accessing password-protected information and did not contain personal or sensitive data. Ethics approval was not required due to the public nature of the internet-based data used. All online content was anonymized in compliance with Chinese data privacy obligations. No personal identifiers were collected. We conducted social listening that complied with ethical considerations based on guidance in China. Confidentiality was maintained throughout the entire project cycle from data collection to reporting.

Web crawlers [19] were designed to extract posts with the keywords amyloid and amyloidosis in Chinese and English; 9330 posts were initially collected. A smaller sample of 7466 posts was acquired from the 9330 posts by manually excluding posts that were (1) not a complete consultation, such as parts of health care articles or concerns of a suspected patient without a doctor’s reply and (2) content that could not be traced to its source due to fee-for-service security in some online medical consultation platforms. Finally, 2204 posts were included in this study.

Figure 1 shows the process for data cleaning from raw data to 2204 valid posts (on the left) and the method for refinement of the natural language processing (NLP) model (on the right).

Manual labeling was implemented for the raw data to optimize the machine learning model. We used 500 valid posts for model refinement instead of all posts to avoid overfitting during machine learning. From the 500 posts, 80% of the labeling results were used as the training set for the model training process, 10% were used as the validation set for model optimization, and the other 10% were used as the test set to evaluate the model in a binary confusion matrix [19]. When all criteria in the matrix were passed, the model was finalized and used for data prediction of all 2024 valid posts, including named entity recognition, relation extraction, and sentiment analysis.

Data transformation was processed with NLP, specifically, a bidirectional encoder representations from transformers (BERT) plus conditional random field (CRF) model, which is an encoder-decoder based codec model proposed by Google. BERT is a language representation model introduced by Google AI Language designed to pretrain deep bidirectional representations from unlabeled text by jointly conditioning on both left and right context in all layers [20]. Combined with a CRF model [21], a popular structured prediction method of classification and graphical modeling, we used named entity recognition and analyzed the sentences for content. The specific content fields for entity recognition included demographic attributes (age, gender, geographical distribution); the organ involved; presentation, examination, and diagnosis; treatment; and follow-up. Next, we used pipelines for entity and relation extraction to parse out the relationships between different entity types from natural text, followed by BERT for sentiment analysis [22].

Descriptive summary statistics were calculated for available demographic and clinical data, and the driving factors and concepts at each key step in the disease diagnosis and treatment journey were deeply explored with machine learning [23]. According to the data mentioned above (Figure 1), we could match these specific data to an identical suspected patient through the source of information, temporal distribution, geographical distribution, and the clinical data. Content from doctors or suspected patients was also annotated and distinguished.

There were 9330 valid consultations and inquiries between January 2008 and April 2021 in total. A total of 2204 posts by suspected patients with AL amyloidosis were included after excluding incorrect or incomplete posts and content not related to AL amyloidosis; 89.29% (n=1968) of these posts were from haodf.com, followed by wy.guahao.com and chunyuyisheng.com (Multimedia Appendix 1, Table S1). The number of online consultations for AL amyloidosis increased every year, reaching 461 in 2020. Geographical distribution showed that Jiangsu (n=260), Zhejiang (n=181), Beijing (n=142), Henan (n=142), Shandong (n=138), Anhui (n=131), Hebei (n=125), Hubei (n=125), Liaoning (n=118 ), and Guangdong (n=115) provinces accounted for 67.01% (n=1477) of the 2204 posts (Multimedia Appendix 1, Table S1).

A total of 1284 posts were made by male users. In 196 posts with valid data for age, the median age was 57 (IQR 46-67) years, ranging from 21 to 87 years. In the pool of 2204 posts, we collected specific symptom-related keywords to evaluate organ involvement in suspected patients with AL amyloidosis. We found that 1459 posts mentioned keywords for renal-related symptoms, followed by heart (n=833), liver (n=491), stomach (n=368), lung (n=306), intestinal (n=280), and nervous system (n=225) symptoms. Furthermore, 1502 suspected patients had 2 or more affected organs (Multimedia Appendix 1, Table S2).

Symptoms varied from patient to patient, and the interval from symptoms to diagnosis for patients with AL amyloidosis was long. Among 2204 posts, weakness, edema, and hypertrophy were the most frequently mentioned symptoms (Table 1). Among 13 posts that mentioned the time from symptom to diagnosis, eight posts reported that they took more than one year to be correctly diagnosed. In many posts, suspected patients reported that they did not consider that the symptoms were related to hematologic disorder when the symptoms began, and they took medicine without a prescription to relieve the discomfort. When the symptoms worsened, it was also difficult to be diagnosed because of the nonspecificity of the symptoms, resulting in frequent intra- and interhospital referrals. A total of 791 posts mentioned the content of the intrahospital referral (Figure 2). Multiple physician visits were reported in posts prior to diagnosis for AL amyloidosis, including to nephrologists, hematologists, cardiologists or neurologists, gastroenterologists, rheumatologists, internists, hepatologists, and otorhinolaryngologists. The first doctor seen was usually a nephrologist (n=265), hematologist (n=214), or cardiologist (n=90). The suspected patients were then often referred for a second visit to a hematologist (n=264), nephrologist (n=124), or cardiologist (n=72). As for interhospital referrals (Figure 3), suspected patients were more likely to go to tertiary hospitals. Local tertiary hospitals (n=513), tertiary hospitals in Beijing and Shanghai (n=316), and tertiary hospitals in cities other than Beijing and Shanghai (n=163) were the most popular choices. Providing an overview of interhospital referrals for suspected patients with AL amyloidosis is complicated; normally, suspected patients are referred between different tertiary hospitals in various cities, except for Beijing and Shanghai residents. Reasons reported in the posts for interhospital referrals included seeking an accurate diagnosis or seeking more effective treatment.

Although AL amyloidosis remains an incurable disease, much progress has been made in the last decade, and important aspects of clinical care for AL amyloidosis patients are guided by evidence-based treatment. Among 1688 posts by doctors mentioning treatment-related keywords, there was an increase in recommendations for bortezomib for the treatment of AL amyloidosis, whereas there was a decline in recommendations for melphalan (Multimedia Appendix 1, Figure S1A). Among 164 posts in which treatment type could be found, bortezomib was recommend as a first-line and second-line treatment by 70% (n=115) and 53% (n=87) of physicians, respectively (Multimedia Appendix 1, Figure S1B).

This is the first study to provide insights into real-world consultation with Chinese patients with AL amyloidosis using a big data technique. We investigated patients’ journeys to an AL amyloidosis diagnosis over more than 10 years, including disease characteristics, patient referrals, diagnoses, and treatments. The main findings of the study are that multiple physician visits and delayed diagnosis were common among patients with AL amyloidosis in the real word.

By comparison to traditional methods based on physician and patient surveys, social listening can collect a large amount of data and provide a comprehensive understanding of real-world settings. The last 5 years have seen a leap in the development of health information technology and social media in China [13]. With 5.25% (88,308/1,680,062) of all doctors in China registered to provide online consultation on haodf.com as of September 23, 2017, online doctors had an average workload of 0.38 patients per doctor per day [18]. The emergence of online consultations provides Chinese patients with a variety of different services, including health problem discussion, health knowledge sharing and searching, diagnosis and treatment, and making appointments and registering [24]. In this study, we included 2204 posts related to AL amyloidosis from online consultations over 13 years (2009-2021). Compared to a systematic review that examined a similar period, our study reflects real-world insights from patients and has built a detailed image of intra- and interhospital referrals. Similarly, the most involved organ was the kidney in Chinese patients with AL amyloidosis, probably because Chinese nephrologists may have more experience of this rare disease than other departments; most papers on Chinese patients with AL amyloidosis are from the renal or hematology departments [25]. Only 38% (n=833) of posts mentioned cardiac-related symptoms in this study, even though cardiac involvement is more common in US patients [26]. Cardiac symptoms may be mistakenly attributed to other cardiac diseases and significantly underdiagnosed [27]. Posts from consultations generated by suspected patients might not differentiate AL amyloidosis–related cardiac symptoms from other cardiac diseases, especially among older posters. An alternative explanation is that posts that were not recognized as describing cardiac symptoms were probably made because the suspected patient or the physician did not ask about or comment on cardiac symptoms. Moreover, whether Chinese patients with AL amyloidosis have a greater susceptibility to renal involvement needs further research.

Weakness, edema, and hypertrophy were the most frequently mentioned symptoms. Likewise, a longitudinal study of community-based patients with AL amyloidosis in the United States found that nonspecific symptoms, such as fatigue and loss of appetite, were reported by 80% of patients [11]. Huang et al [9] reported that Chinese patients primarily presented with fatigue (40%) and edema (81%) at the time of diagnosis, followed by orthostatic hypotension (30%) and weight loss (27%), while in US health care institutions, the most common signs and symptoms are malaise or fatigue (61%) and dyspnea (59%) [26].

Our analysis indicates that patients experienced long journeys, visiting different departments and different hospitals until being correctly diagnosed; thus, delayed diagnoses were commonly seen in patients with AL amyloidosis. McCausland et al [11] conducted a longitudinal, noninterventional study of community-based patients with AL amyloidosis. They found that nearly 43% of patient interviewees needed more than 12 months from the onset of symptoms to a confirmed diagnosis, and 43% of patients had consulted 5 or more doctors before diagnosis [11]. In our study, 8 of 13 patients declared that they were diagnosed before 1 year after the onset of symptoms. Reflecting our results as well as those of the survey by McCausland et al [11], patients’ interpretation of their initial symptoms, timing of seeking medical help, and challenges in differential diagnoses might be barriers to diagnosis for AL amyloidosis. Symptoms of AL amyloidosis are often misinterpreted as aging or other more common chronic ailments; thus, more attention should be paid to potential AL amyloidosis–related signs and symptoms at an early stage.

We found that patients were concentrated in top-tier hospitals in major cities and that hematologists and nephrologists in tertiary hospitals had the most opportunities to reach patients with AL amyloidosis. Discriminating AL amyloidosis from common diseases and other types of amyloidosis is difficult because AL amyloidosis is not only a rare disease, but is typically a multisystem disease, resulting in complex signs and symptoms with different systems involved [28,29]. As tertiary hospitals have abundant medical resources such as advanced diagnostic modalities and experienced physicians to support early recognition of rare diseases, early referral to a specialized center with expertise in management of AL amyloidosis is always recommended [29].

There are several limitations to this analysis. First, the data were collected from online doctor-patient communication platforms in China, but it is unclear whether the results of this study can be generalized to represent all AL amyloidosis patients even within China due to selection bias arising from the inclusion of only internet users. Second, the available data were constrained by what patients posted, possibly leading to inaccuracies and skewed data. Third, although we eliminated as many non-AL amyloidosis patients as possible, it is inevitable that we included other types of amyloidosis, as the patients were not clinically validated. Despite these limitations, this study offers a large sample of a rare disease and comprehensive insights that increase understanding of the real-world patient journey for AL amyloidosis in China.

This study explored clinical characteristics and patient experience from symptom onset to diagnosis of AL amyloidosis in China. Patients experience referrals during their journey to an accurate diagnosis. Increasing awareness of the disease and early referral to a specialized center with expertise may reduce delayed diagnoses and improve patient management. For precise treatments, further evidence-based research on AL amyloidosis in China is required.