Public interest in Raynaud's phenomenon: A Google Trends analysis

Raynaud's phenomenon is a common disorder affecting body extremities and other vascular beds. As infodemiological methods have developed, online search tools could be used to explore the public interest of the disease. The study aimed to determine the annual trend, seasonal pattern, and associated topics of Raynaud's phenomenon. Google Trends was used to collect the data. “Raynaud syndrome” was selected as the search term. Data on monthly relative search volume (RSV) were collected from four selected countries (United States, United Kingdom, Australia, and New Zealand) and globally. Related topics were obtained, and annual‐related topics were also collected for analysis. The maximum RSV appeared in January 2019, and the minimum value was observed in August 2011. The peak for RSV occurred in winter, and the bottom appeared in summer. In top related topics, “Maurice Raynaud” was the most related. In rising related topics, disease manifestations and autoimmune connective diseases were highly concerned. For annual‐related topics, associated diseases were attracting more attention over time. The population is interested in related diseases, pathogenesis, and treatment. There was a peak in winter for searching and supported the importance of season variation on the impact of Raynaud's phenomenon.


| INTRODUCTION
Raynaud's phenomenon is a common vasospasm response to cold or emotional stress, causing characteristic cutaneous color changes in the digits. 1 It affects more women than men, and the prevalence of Raynaud's phenomenon was estimated from 3% to 5% in most population-based surveys. 2,3 It can be idiopathic or secondary to another disease, including autoimmune connective tissue diseases.
Identifying Raynaud's phenomenon is also of importance in the early diagnosis of connective tissue diseases, for example, the systemic sclerosis. 4 Primary and secondary Raynaud's phenomenon have different disease onset ages, patterns, pathogenesis, and prognosis. 2,5 The quality of life of the patients may be severely reduced, 6 but many people with Raynaud's phenomenon do not go to the clinics to seek professional medical advice. 7 Nowadays, patients increasingly use the Internet to search for health-related information, which may influence medical decision-making. 8 Therefore, infodemiological methods are becoming more and more competitive to estimate the disease epidemiological characteristics, to explore the public awareness of the management and treatment, and especially to detect and monitor the public interest of the disease. 9 Currently, the most frequently used tool in addressing health issues related to Internet data is Google Trends. Researchers have conducted a lot of research using Google Trends in the rheumatology and immunology area, including systemic lupus erythematosus, 10 rheumatoid arthritis, 11 and multiple sclerosis. 12 Recently, Hughes M. demonstrated that there existed a seasonal fluctuation on Internet searches in Yuanzhuo Wang and Hanlin Zhang have contributed equally to this study. They are co-first authors and also considered as joint authors.
Raynaud's phenomenon. 13 However, the overall trends, geographic distribution, and associate topics have not been completely elucidated.
We collected the data from Google Trends and analyzed the trends to further illustrate the public interest.

| Searching tool and Keyword selection
Google Trends was used to collect data. Time and country could be restricted for comparison in Google Trends. A scale from 0 to 100 was used to represent the relative search volume (RSV) of a specific search term. A 100 value represents the highest RSV in a defined time period, and a value of 0 does not necessarily indicate no searches, but rather extremely low RSV.
The search term was chosen under the recommendation of a former guideline. 14 The guideline explained the "Topics" as a group of terms that share the same concept in any language automatically judged by the Google Trends, 14 which may contain the most associated information. In our research, Google Trends did not provide a topic that contains the search term "Raynaud's phenomenon." Instead, "Raynaud syndrome" was given as a topic, which included all information from the search term "Raynaud's phenomenon." After comparing the average RSV of "Raynaud syndrome" as a medical condition (a topic) and the sum of several related keywords as the term (Raynaud + Raynaud's + Raynaud phenomenon + Raynaud's phenomenon + Raynaud syndrome + Raynaud's syndrome), the former one was finally selected, for it produced a higher value of the average RSV and indicated that it may include many other related searches in non-English speaking countries. (https://support.google. com/trends/answer/4359550?hl=en&ref_topic=4365530).

| Data query
The time range was set from January 2004 to December 2019. The "Health" category was selected to exclude irrelevant information like brand names. Results of regions whose RSV was lower than 5 were automatically excluded in the heat map of RSV among countries and regions. On March 5, 2020, data of the "Worldwide" RSV were exported to Microsoft Excel 2019.
Related topics of the search term from Google Trends were also extracted. Google Trends provided two types of related topics. One is the "Top related topics," defined as the most frequently searched topics within the chosen category, time, or country. The other is the "Rising related topics," which had the highest growth in volume and was presented as a percentage of fold changes. Non-related results were excluded manually. To examine the variation of the related topics over time, we further queried and analyzed the annual "Top related topics" and "Rising related topics." The top three topics were selected for analysis.
For seasonal variation analysis, four countries whose official language was English were included. United States, United Kingdom were the representatives from the Northern hemisphere, while Australia and New Zealand were the samples from the Southern hemisphere. The average annual temperature of the United States was retracted from the National Oceanic and Atmospheric Administration (NOAA, https://www.ncdc.noaa.gov/).

| Statistical analysis
All analysis was conducted on the R software (v 3.6.2), and the graphs were directly obtained from the plotting function of R. The average monthly RSV in a year was calculated. A smooth curve was then added to the algorithm using the "spline" function in R. A cosinor model was used for seasonal analysis according to Barnett's research. 15 A "season" package was applied to produce boxplots of seasonal variation for different countries. The Pearson method was used to calculate the correlation coefficient. A P value <.05 was considered statistically significant.

| Ethical requirements
This study did not involve animal experiments or clinical trials. Thus, permission from the ethical committee was not needed.

| Seasonal variation
All curves were fitted with the "cosinor" model in Figure 2 (all P value <.05), which showed the seasonal variation for the RSV. The analysis revealed that the peak for the RSV in Raynaud's phenomenon   Table S1. Overall, a country or region in higher latitude may yield more RSV than that in lower latitudes.

| DISCUSSION
Raynaud's phenomenon is characterized as painful vasospasm of small arteries localized in distant body extremities, and its pathogenesis has not been completely elucidated. 16,17 The Internet is being widely used for seeking health information nowadays, with about a third of the population in the world depending on it. 18 Recently, infodemiological methods were demonstrated to be competitive in providing real-time monitoring of psychological and behavioral outcomes in the medical and health area. 19 The use of search engines is also associated with a physician visit and serves as a supplement to health care services. 20 Google Trends is particularly useful, for it offers several valuable insights into the health information-seeking behavior and collects the Internet activities concerning a specific topic. [21][22][23] This study applied Google Trends to evaluate public interest in Besides, a country or region with higher latitude may have RSV far more than average, for they have a lower temperature, which may be important precipitating factors of Raynaud's phenomenon.
When it comes to related topics, the top is Maurice Raynaud, a French physician who discovered Raynaud's phenomenon in his doctoral thesis. 27 Besides, Raynaud's phenomenon is often the first clinical manifestation of connective tissue diseases. 28 29 "Hand", "paresthesia", "syndrome", "disease" are the terms associated with the location or manifestation of the disease. The rising topic shows the transition of the public focus.
Before 2014, people searched for more health information on the Internet concerning the manifestations and management of Raynaud's phenomenon. This was consistent with the research hot spot, for early research was always to explore and identify the clinical syndromes, such as paresthesia and acrocyanosis. 37 Therapy for this disease also attracted much attention, such as pharmacotherapy of nitroglycerin or pentoxifylline, 38,39 and surgical method like endoscopic thoracic sympathectomy. 40 In recent years, more searches focused on the pathogenesis and associated diseases. These topics were also mentioned in the publication of the latest articles which elucidated the possible molecular mechanisms and associated diseases. 28 The seasonal analysis could provide extra evidence. The previous study had demonstrated the seasonal pattern of the RSV in Raynaud's phenomenon. 13 We separately analyzed four different countries and tried to broaden the conclusion globally. The monthly RSV shows peaks in winter for both the northern and southern hemisphere countries, with low points in summer correspondingly. This might illustrate that temperature could be a key factor leading to Raynaud's phenomenon, partially explained disease development, severity, and progression. This also demands future clinical research to evaluate the effect of seasonal variation. 13 Hughes had already emphasized the impact of seasonal variation on clinical researches in Raynaud's phenomenon. 13 It could be better to test new treatments and therapies in the winter. This means that there also exist challenges for clinical trials to measure treatment efficacy and short duration clinical trails or using diary-based approaches instead of long duration observations are more warranted to avoid the effect of the weather.
Although the pathogenesis of Raynaud's phenomenon has not been completely elucidated, the possible molecular mechanisms had been discussed in detail. In individuals affected by Raynaud's phenomenon, long-lasting vasoconstriction will result in clinical symptoms, ranging from general discomfort to serious, disabling conditions. 2 Dysregulation of autonomic and small sensory nerve fibers, involving the abnormal release of several chemical substances (calcitonin generelated peptide, neurokinin A, substance P, vasoactive intestinal peptide, adrenergic agonists, and nerve growth factor), leads to abnormal vasoconstriction of peripheral small vessels. 28 The severe fibrotic proliferation of the intima and other structural abnormalities secondary to connective tissue diseases are the fundamental changes causing secondary Raynaud's disease. 41 Increased levels of endothelin-1